Pyrimidines as PLK inhibitors

ABSTRACT

The present invention encompasses compounds of general formula (1), 
     
       
         
         
             
             
         
       
     
     wherein
 
A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 are defined as in claim  1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.

The present invention relates to new pyrimidines of general formula (1),

wherein the groups A, W, X, Y, Z, R^(a), R^(b), R^(c), R¹ and R³ havethe meanings given in the claims and description, the isomers thereof,processes for preparing these pyrimidines and their use aspharmaceutical compositions.

BACKGROUND TO THE INVENTION

Tumour cells wholly or partly elude regulation and control by the bodyand are characterised by uncontrolled growth. This is due on the onehand to the loss of control proteins such as for example Rb, p16, p21and p53 and also to the activation of so-called accelerators of the cellcycle, the cyclin-dependent kinases.

Studies in model organisms such as Schizosaccharomyces pombe, Drosophilamelanogaster or Xenopus laevis as well as investigations in human cellshave shown that the transition from the G2 phase to mitosis is regulatedby the CDK1/cyclin B kinase (Nurse 1990, Nature 344: 503-508). Thiskinase, which is also known as “mitosis promoting factor” (MPF),phosphorylates and regulates a plurality of proteins, such as e.g.nuclear lamina, kinesin-like motor proteins, condensins and Golgi MatrixProteins, which play an important part in the breakdown of the nuclearcoat, in centrosome separation, the structure of the mitotic spindleapparatus, chromosome condensation and breakdown of the Golgi apparatus(Nigg. E. 2001, Nat Rev Mol Cell Biol. 2(1):21-32). A murine cell linewith a temperature-sensitive CDK-1 kinase mutant shows a rapid breakdownin CDK-1 kinase after temperature increase and a subsequent arrest inthe G2/M phase (Th'ng et al. 1990, Cell. 63(2):313-24). The treatment ofhuman tumour cells with inhibitors against CDK1/cyclin B, such as e.g.butyrolactone, leads to an arrest in the G2/M phase and subsequentapoptosis (Nishio, et al. 1996, Anticancer Res. 16(6B):3387-95).

Moreover, the protein kinase Aurora B has also been described as havingan essential function during entry into mitosis. Aurora B phosphorylateshistone H3 on Ser 10 and thereby initiates chromosome condensation (Hsuet al. 2000, Cell 102:279-91). A specific cell cycle arrest in the G2/Mphase may, however, also be initiated e.g. by inhibition of specificphosphatases such as e.g. Cdc25C (Russell and Nurse 1986, Cell45:145-53). Yeasts with a defective Cdc25 gene arrest in the G2 phase,whereas overexpression of Cdc25 leads to premature entry into themitosis phase (Russell and Nurse, 1987, Cell 49:559-67). Moreover, anarrest in the G2/M phase may also be initiated by inhibition of specificmotor proteins, the so-called kinesins such as for example Eg5 (Mayer etal. 1999, Science 286:971-4), or by microtubuli stabilising ordestabilising agents (e.g. colchicin, taxol, etoposide, vinblastine,vincristine) (Schiff and Horwitz 1980, Proc Natl Acad Sci USA77:1561-5).

In addition to the cyclin-dependent and Aurora kinases the so-calledpolo-like kinases, a small family of serine/threonine kinases, also playan important role in the regulation of the eukaryotic cell cycle. Uptill now the polo-like kinases PLK-1, PLK-2, PLK-3 and PLK-4 have beendescribed in the literature. PLK-1 in particular has been found to playa central role in the regulation of the mitosis phase. PLK-1 isresponsible for the maturation of the centrosomes, for the activation ofphosphatase Cdc25C, as well as for the activation of the AnaphasePromoting Complex (Glover et al. 1998, Genes Dev. 12:3777-87; Qian etal. 2001, Mol Biol Cell. 12:1791-9). The injection of PLK-1 antibodiesleads to a G2 arrest in untransformed cells, whereas tumour cells arrestduring the mitosis phase (Lane and Nigg 1996, J. Cell Biol.135:1701-13). Overexpression of PLK-1 has been demonstrated in varioustypes of tumour, such as non-small-cell carcinoma of the lung, plateepithelial carcinoma, breast and colorectal carcinoma (Wolf et al. 1997,Oncogene 14:543-549; Knecht et al. 1999, Cancer Res. 59:2794-2797; Wolfet al. 2000, Pathol. Res. Pract. 196:753-759; Takahashi et al. 2003,Cancer Sci. 94:148-52). Therefore, this category of proteins alsopresents an interesting point of attack for therapeutic intervention inproliferative diseases (Liu and Erikson 2003, Proc Natl Acad Sci USA100:5789-5794).

Pyrimidines are generally known as inhibitors of kinases. Thus, forexample, pyrimidines are described as an active component with ananticancer activity in International Patent Application WO 00/53595,which describes the use of 2,4,5-substituted pyrimidines with aheterocyclic group in the 4-position and an anilino group in the 2position, which in turn comprises a side chain with the length of atleast one n-propyl group.

Moreover, International Patent Application WO 00/39101 describes the useof 2,4,5-substituted pyrimidines as compounds with an anticanceractivity which are linked in the 2- and 4-position with an aromatic orheteroaromatic ring, at least one of which comprises a side chain withthe length of at least one n-propyl group.

International Patent Application WO 97/19065 further proposes the use of2,4,5-substituted pyrimidines with a 3,4-dialkoxyanilino group inposition 2 as kinase inhibitors.

International Patent Application WO 02/04429 describes 2,4,5-substitutedpyrimidines with a cyano group in position 5 and their cell cycleinhibiting effect.

International Patent Application WO 03/063794 describes the use of2,4-pyrimidinediamines as inhibitors of the IgE and/or IgG receptorsignal cascade.

Antiviral 2,4,5-substituted pyrimidines, wherein the groups R^(c) andR^(d) form a heteroaromatic five-membered ring at the nitrogen of the4-position, are known from International Patent Application WO 99/41253.

2,4,5-substituted pyrimidines which carry (hetero)aryls in position 2and 4 (WO00/27825) and also 2,4,5-substituted pyrimidines which carry a(hetero)aryl group functionalised with a nitrile group in position 2 or4 (EP 0 945 443 A1) are described as having an antiviral activity.

The resistance of many types of tumour demands that new drugs bedeveloped to fight the tumours. The aim of the present invention istherefore to indicate new active substances which may be used for theprevention and/or treatment of diseases characterised by excessive oranomalous cell proliferation.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that, surprisingly, compounds of general formula(I), wherein the groups A, W, X, Y, R^(a), R^(b), R^(c), R¹, R² and R³are defined as hereinafter, act as inhibitors of specific cell cyclekinases. Thus, the compounds according to the invention may be used forexample for the treatment of diseases associated with the activity ofspecific cell cycle kinases and characterised by excessive or anomalouscell proliferation.

The present invention relates to compounds of general formula (1)

wherein

-   W denotes N or C—R²,-   X denotes —NR^(1a), O or S,-   Y denotes CH or N,-   Z denotes hydrogen, halogen, —NO₂, C₁₋₃alkyl, C₂₋₃alkenyl,    C₂₋₃alkynyl, halogen-C₁₋₃alkyl, —COH, —C(═O)—C₁₋₃alkyl,    —C(═O)—C₂₋₃alkenyl, —C(═O)—C₂₋₃alkynyl, —C(═O)C₁₋₃alkyl-halogen or    pseudohalogen;-   A is selected from the formulae (i), (ii) or (iii)

-   Q₁ denotes mono- or bicyclic aryl compounds;-   B¹, B², B³ and B⁴ in each case independently of one another denote    C—R^(g)R^(h), N—R^(i), O or S, while adjacent B¹-B⁴ in each case do    not represent —O—;-   R¹ and R^(1a) each independently of one another denote hydrogen or    methyl,-   R² denotes a group selected from among hydrogen, halogen, —OR⁴,    —C(═O)R⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵,    —C═NR^(i), —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵ and pseudohalogen, or an    optionally mono- or polysubstituted group selected from among    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆-cycloalkyl, aryl,    heterocyclyl and heteroaryl, while the substituent(s) may be    identical or different and are selected from among halogen, —NO₂,    —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵,    —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴,    —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen;-   R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g) and R^(h) in each    case independently of one another denote a group selected from among    hydrogen, halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵,    —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵,    —N═CR⁴R⁵, —C═NR^(i), —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶,    —OSO₂NR⁵R⁶ and pseudohalogen; group functionalised with a nitrile    group in position 2 or 4 (EP 0 945 443 A1) are described as having    an antiviral activity.

The resistance of many types of tumour demands that new drugs bedeveloped to fight the tumours. The aim of the present invention istherefore to indicate new active substances which may be used for theprevention and/or treatment of diseases characterised by excessive oranomalous cell proliferation.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that, surprisingly, compounds of general formula(I), wherein the groups A, W, X, Y, R^(a), R^(b), R^(e), R¹, R² and R³are defined as hereinafter, act as inhibitors of specific cell cyclekinases. Thus, the compounds according to the invention may be used forexample for the treatment of diseases associated with the activity ofspecific cell cycle kinases and characterised by excessive or anomalouscell proliferation.

The present invention relates to compounds of general formula (1)

wherein

-   W denotes N or C—R²,-   X denotes —NR^(1a), O or S,-   Y denotes CH or N,

-   R⁴, R⁵ and R⁶ each independently of one another denote hydrogen or a    group selected from among optionally mono- or polysubstituted    C₁₋₅-alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, C₃₋₁₀cycloalkyl, aryl,    heterocyclyl and heteroaryl, while the substituent(s) may be    identical or different and are selected from among C₃₋₁₀-cycloalkyl,    aryl, heterocyclyl, heteroaryl, halogen, —NO₂, —OR⁸, —C(═O)R⁸,    —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,    —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸,    —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   L denotes a bond or a group selected from among optionally mono- or    polysubstituted C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,    C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the    substituent(s) may be identical or different and are selected from    among halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹,    —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰,    —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰,    —OSO₂NR⁸R⁹ and pseudohalogen;-   Q₂ and Q₃ independently of one another denote a bond or a group    selected from among optionally mono- or polysubstituted C₁₋₁₆-alkyl,    C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl    and heteroaryl while the substituent(s) may be identical or    different and are selected from among halogen, —NO₂, —OR⁸, —C(═O)R⁸,    —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,    —NR⁸C(═O)NR⁹R¹⁰, NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸,    —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   R⁷ denotes hydrogen or a group selected from among optionally mono-    or polysubstituted C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,    C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the    substituent(s) may be identical or different and are selected from    among halogen, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹,    —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰,    —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR^(B), —SO₂R⁸, —SO₂NR⁸R⁹,    —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   R⁸, R⁹ and R¹⁰ each independently of one another denote hydrogen or    a group selected from among optionally substituted C₁₋₈-alkyl,    C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and    heteroaryl, while the substituent(s) may be identical or different    and are selected from among halogen, methyl, ethyl, amino,    methylamino, dimethylamino, —OH and pseudohalogen;    optionally in the form of the tautomers, racemates, enantiomers,    diastereomers and mixtures thereof, and optionally the    pharmacologically acceptable acid addition salts thereof.

In one aspect the invention relates to compounds of general formula (I)wherein

-   W denotes C—R² and the other groups are as hereinbefore defined.

In another aspect the invention relates to compounds of general formula(I), wherein

-   X denotes —NR^(1a) or oxygen,-   R¹ and R^(1a) denote hydrogen;-   R³ denotes formula (Iv) or (x),

and the other groups are as hereinbefore defined.

In another aspect the invention relates to compounds of general formula(I), wherein

-   Y denotes CH and-   Q₁ denotes monocyclic aryl compounds    and the other groups are as hereinbefore defined.

In one aspect the invention relates to compounds of general formula (I),wherein

-   R^(c) denotes a group selected from among hydrogen, —F, —Cl, methyl    and ethyl and the other groups are as hereinbefore defined.

In another aspect the invention relates to compounds of general formula(I), wherein

-   R^(a) and R^(b) each independently of one another denote hydrogen or    fluorine;    -   or an optionally mono- or polysubstituted group selected from        among C₁₋₂-alkyl, C₂-alkenyl, C₂-alkynyl, C₃₋₆-cycloalkyl, aryl,        heterocyclyl and heteroaryl, while the substituent(s) may be        identical or different and are selected from among hydrogen,        halogen, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵,        —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵,        —SR⁴, —SOR⁵, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴, —SO₂NR⁴R⁵, —OSO₂NR⁴R⁵ and        pseudohalogen        and the other groups are as hereinbefore defined.

In another aspect the invention also relates to compounds of generalformula (I), wherein

R^(a) and R^(b) denote hydrogen or fluorine and the other groups are ashereinbefore defined.

The invention also includes compounds of general formula (I), wherein

-   Z denotes halogen-C₁₋₃-alkyl, —COH, —C(═O)—C₁₋₃-alkyl,    —C(═O)—C₂₋₃-alkenyl, —C(═O)—C₂₋₃-alkynyl, —C(═O)C₁₋₃-alkyl-halogen    and pseudohalogen    and the other groups are as hereinbefore defined.

In one aspect the invention relates to compounds of general formula (I),or the pharmaceutically active salts thereof, as pharmaceuticalcompositions.

In an essential aspect the invention relates to compounds of generalformula (I), or the pharmaceutically active salts thereof, for use aspharmaceutical compositions with an antiproliferative activity.

Moreover the invention includes compounds of general formula (I), or thepharmaceutically active salts thereof, for use as pharmaceuticalcompositions with an antiproliferative activity with a selectivekinase-inhibiting mechanism of activity.

In one aspect the invention relates to the use of compounds of generalformula (I), or the pharmaceutically active salts thereof, for preparinga pharmaceutical composition with an antiproliferative activity with aPLK inhibiting mechanism of activity.

In another aspect the invention relates to pharmaceutical preparations,containing as active substance one or more compounds of general formula(I), or the physiologically acceptable salts thereof, optionally inconjunction with conventional excipients and/or carriers.

In another aspect the invention relates to the use of one or morecompounds of general formula (I) for preparing a pharmaceuticalcomposition for the treatment and/or prevention of cancer, infections,inflammatory and autoimmune diseases.

In another aspect the invention relates to a pharmaceutical preparationcontaining at least one compound of general formula (I)

wherein

-   W denotes N or C—R²,-   X denotes —NR^(1a), O or S,-   Y denotes CH or N,-   Z denotes hydrogen, halogen, —NO₂, C₁₋₃-alkyl, C₂₋₃-alkenyl,    C₂₋₃-alkynyl, halogen-C₁₋₃-alkyl, —COH, —C(═O)—C₁₋₃-alkyl,    —C(═O)—C₂₋₃-alkenyl, —C(═O)—C₂₋₃-alkynyl, —C(═O)C₁₋₃-alkyl-halogen    and pseudohalogen;-   A is selected from the formulae (i), (ii) or (iii)

-   Q₁ denotes mono- or bicyclic aryl compounds;-   B¹, B², B³ and B⁴ in each case independently of one another    represent C—R^(g)R^(h), N—R^(i), O or S, while adjacent B¹-B⁴ in    each case do not denote —O—;-   R¹ and R^(1a) each independently of one another denote hydrogen or    methyl,-   R² denotes a group selected from among hydrogen, halogen, —OR⁴,    —C(═O)R⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵,    —C═NR^(i), —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵ and pseudohalogen, or an    optionally mono- or polysubstituted group selected from among    C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, aryl,    heterocyclyl and heteroaryl, while the substituent(s) may be    identical or different and are selected from among halogen, —NO₂,    —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵,    —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴,    —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen;-   R^(a), R^(b), R^(e), R^(d), R^(e), R^(f), R^(g) and R^(h) in each    case independently of one another denote a group selected from among    hydrogen, halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C═O)OR⁴, —C(═O)NR⁴R⁵,    —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵,    —N═CR⁴R⁵, —C═NR^(i), —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶,    —OSO₂NR⁵R⁶ and pseudohalogen;    -   or an optionally mono- or polysubstituted group selected from        among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,        aryl, heterocyclyl and heteroaryl, while the substituent(s) may        be identical or different and are selected from among halogen,        R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵,        —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵,        —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and        pseudohalogen; and optionally the R^(g) and R^(h) located at the        same or at adjacent C atoms may be attached in any combination        to a common saturated or partially unsaturated 3-5-membered        alkyl bridge which may contain one to two heteroatoms;-   R^(i) denotes a group selected from among hydrogen, ═O)—OR⁴,    —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵,    —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵,    —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ or an optionally mono- or polysubstituted    group selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₆-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the    substituent(s) may be identical or different and are selected from    among halogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵,    —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵,    —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶    and pseudohalogen; and optionally the Ri groups located at adjacent    N atoms may be joined together or to R^(g) and R^(h) located at    adjacent C atoms in any combination with a common saturated or    partially unsaturated 3-5-membered alkyl bridge which may contain    one to two heteroatoms;-   R³ is selected from the formulae (iv)-(x),

-   R⁴, R⁵ and R⁶ each independently of one another denote hydrogen or a    group selected from among optionally mono- or polysubstituted    C₁₋₅-alkyl, C₂₋₅-alkenyl, C₂₋₅-alkynyl, C₃₋₁₀-cycloalkyl, aryl,    heterocyclyl and heteroaryl, while the substituent(s) may be    identical or different and are selected from among C₃₋₁₀-cycloalkyl,    aryl, heterocyclyl, heteroaryl, halogen, —NO₂, —OR⁸, —C(═O)R⁸,    —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,    —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸,    —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   L denotes a bond or a group selected from among optionally mono- or    polysubstituted C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,    C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the    substituent(s) may be identical or different and are selected from    among halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹,    —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰,    —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR^(B), —SO₂R⁸, —SO₂NR⁸R⁹,    —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   Q₂ and Q₃ independently of one another denote a bond or a group    selected from among optionally mono- or polysubstituted C₁₋₁₆-alkyl,    C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl    and heteroaryl, while the substituent(s) may be identical or    different and are selected from among halogen, —NO₂, —OR⁸, —C(═O)R⁸,    —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,    —NR⁸C(═O)NR⁹R¹⁰NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸,    —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   R⁷ denotes hydrogen or a group selected from among optionally mono-    or polysubstituted C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,    C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, while the    substituent(s) may be identical or different and are selected from    among halogen, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹,    —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰,    —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR^(B), —SO₂R⁸, —SO₂NR⁸R⁹,    —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen;-   R⁸, R⁹ and R¹⁰ each independently of one another denote hydrogen or    a group selected from among optionally substituted C₁₋₈-alkyl,    C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and    heteroaryl, while the substituent(s) may be identical or different    and are selected from among halogen, —NH₂, —OH and pseudohalogen;    optionally in the form of the tautomers, racemates, enantiomers,    diastereomers and mixtures thereof, and optionally the    pharmacologically acceptable acid addition salts thereof, and    at least one other cytostatic or cytotoxic active substance,    optionally in the form of the tautomers, racemates, enantiomers,    diastereomers and mixtures thereof, and optionally the    pharmacologically acceptable acid addition salts thereof.

DEFINITIONS

As used herein, the following definitions apply, unless statedotherwise.

By alkyl substituents are meant in each case saturated, straight-chainor branched aliphatic hydrocarbon groups (alkyl group).

The alkenyl substituents are in each case straight-chain or branched,unsaturated alkyl groups which have at least one double bond.

By alkynyl substituents are meant in each case straight-chain orbranched, unsaturated alkyl groups which have at least one triple bond.

Haloalkyl refers to alkyl groups wherein one or more hydrogen atoms arereplaced by halogen atoms. Haloalkyl includes both saturated alkylgroups and unsaturated alkenyl and alkynyl groups, such as for example—CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃,—CF₂CF₂CF₃, —CF₂CH₂CH₃, —CHFCH₂CH₃ and —CHFCH₂CF₃.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

By pseudohalogen are meant the following groups: —OCN, —SCN, —CF₃ and—CN.

By cycloalkyl is meant a mono- or bicyclic ring, while the ring systemmay be a saturated ring or an unsaturated, non-aromatic ring, which mayoptionally also contain double bonds, such as for example cyclopropyl,cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, spiro[5.5]undecane,spiro[5.4]decane and spiro[4.4]nonane.

Aryl relates to monocyclic or bicyclic rings with 6-12 carbon atoms suchas for example phenyl and naphthyl.

By heteroaryl are meant mono- or bicyclic rings which contain instead ofone or more carbon atoms one or more identical or different heteroatoms,such as e.g. nitrogen, sulphur or oxygen atoms. Examples include furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl. Examples ofbicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl,benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl,indolizinyl, oxazolopyridinyl, imidazopyridinyl, naphthyridinyl,indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, cumarinyl,isocumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxid,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocumarinyl, dihydroisocumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide,isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide,phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide,oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide,pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide andbenzothiopyranyl-S,S-dioxide.

Heterocyclyl relates to saturated or unsaturated, non-aromatic mono-,bicyclic or bridged bicyclic rings comprising 5-12 carbon atoms, whichcarry heteroatoms, such as nitrogen, oxygen or sulphur, instead of oneor more carbon atoms. Examples of such heterocylyl groups aretetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,indolinyl, isoindoliny, morpholinyl, thiomorpholinyl, homomorpholinyl,homopiperidyl, homopiperazinyl, thiomorpholinyl-S-oxide,thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, piperidinyl,tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-5-oxide, 2-oxa-5-azabicyclo[2.2.1]heptane,8-oxa-3-aza-bicyclo[3.2.1]octane, 3,8-diaza-bicyclo[3.2.1]octane,2,5-diaza-bicyclo[2.2.1]heptane, 3,8-diaza-bicyclo[3.2.1]octane,3,9-diaza-bicyclo[4.2.1]nonane, 2,6-diaza-bicyclo[3.2.2]nonane,2,7-diaza-spiro[3.5]nonane, 2,7-diaza-spiro[4.4]nonane,2,8-diaza-spiro[4.5]decane, 3,9-diaza-spiro[5.5]undecane.

The Examples that follow illustrate the present invention withoutrestricting its scope:

Preparation of the Compounds According to the Invention:

The compounds according to the invention may be prepared according tomethods of synthesis A to C described hereinafter, wherein thesubstituents of general formulae (I to XVI) have the meanings givenhereinbefore.

Method A Step 1A

The intermediate compound III is prepared by substitution of a leavinggroup LG, for example halogen, SCN or methoxy, preferably chlorine, in aheteroaromatic system I by a nucleophile II.

1 equivalent of compound I and 1 to 1.5 equivalents of compound II arestirred in a solvent, for example 1,4-dioxane, tetrahydrofuran, ethanol,isopropanal, N,N-dimethylformamide or N,N-dimethylacetamide. At atemperature of 15 to 25° C., 2 to 2.5 equivalents of a base, for examplepotassium carbonate, sodium carbonate, caesium carbonate,N-ethyl-N,N-diisopropylamine or triethylamine, are added. The reactionmixture is stirred for 6 to 72 h at a temperature of 20 to 100° C. Thenthe solvent is distilled off and the residue is combined with waterwhich has been adjusted to a pH of between 1-4 with an inorganic acid,for example hydrochloric acid or sulphuric acid. This mixture isextracted two to three times with an organic solvent, for examplediethyl ether, ethyl acetate or dichloromethane. The combined organicextracts are dried and the solvent is distilled off. The residue ispurified by chromatography.

Step 2A

The end compound V is prepared by substitution of a leaving group LG,for example halogen, SCN or methoxy, preferably chlorine, in aheteroaromatic system III by a nucleophile IV.

1 equivalent of the compound III and 1 to 3 equivalents of the compoundIV are stirred in a solvent, for example 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide orN-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 1 to 2equivalents of an inorganic acid, for example sulphuric acid orhydrochloric acid, are added. The reaction mixture is stirred foranother 12 to 72 h at a temperature of 20 to 100° C. Then the solvent isdistilled off and the residue is purified by chromatography.

Method B Step 1B

The intermediate compound VII is prepared by substitution of a leavinggroup LG, for example halogen, SCN, methoxy, preferably chlorine, in aheteroaromatic system I by a nucleophile VI.

1 equivalent of the compound I and 1 to 1.5 equivalents of the compoundVI are stirred in a solvent, for example 1,4-dioxane, tetrahydrofuran,ethanol, isopropanol, N,N-dimethylformamide or N,N-dimethylacetamide.

At a temperature of 15 to 25° C., 2 to 2.5 equivalents of a base, forexample potassium carbonate, sodium carbonate, caesium carbonate,potassium hydrogen phosphate, N-ethyl-N,N-diisopropylamine ortriethylamine are added. The reaction mixture is stirred for 6 to 72 hmore at a temperature of 20 to 120° C. The reaction mixture is combinedwith water, which has been adjusted to a pH of 8 to 9 with an inorganicbase, for example sodium hydrogen carbonate or potassium carbonate. Thismixture is extracted two to three times with an organic solvent, forexample diethyl ether or ethyl acetate.

The combined organic extracts are dried and the solvent is distilledoff. The residue is purified by chromatography or repeatedcrystallisation.

Step 2B

The intermediate compound VIII is prepared by substituting a leavinggroup LG, for example halogen, SCN, methoxy, preferably chlorine, in aheteroaromatic system VII by a nucleophile IV.

1 equivalent of the compound VII and 1 to 1.5 equivalents of thecompound IV are stirred in a solvent, for example 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide orN-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C., 0.2 to 1equivalent of an acid, for example sulphuric acid or hydrochloric acid,is added. The reaction mixture is stirred for another 12 to 72 h at atemperature of 20 to 100° C. The reaction mixture is stirred into waterand the resulting precipitate is filtered off and dried. The precipitatemay be purified by chromatography or crystallisation or used as thecrude product in the next step.

Step 3B

Compounds VIII whose group R⁷ denotes hydrogen may be used directly forpreparing the end compounds X, while a compound VIII is reacted with acompound IX.

Compounds VIII whose group R⁷ does not denote hydrogen are convertedbeforehand by hydrolysis or similar methods known to the skilled maninto the compounds wherein the group R⁷ denotes hydrogen.

1 equivalent of the compound VIII, 1 to 1.5 equivalents of the compoundI× and 1 to 3 equivalents of a base, for example triethylamine orethyldiisopropylamine, are stirred in a solvent, for example1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide orN-methyl-2-pyrrolidinone. At a temperature of 15 to 25° C., 1 to 1.5equivalents of a coupling reagent, for exampleN,N-dicyclohexylcarbodiimide, N,N-diisopropyl-carbodiimide,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate or1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide are added. Thereaction mixture is stirred for another 4 to 24 h at a temperature of 15to 25° C. Then the solvent is distilled off and the residue is purifiedby chromatography.

Method C Step 1C

The intermediate compound XI is prepared by substituting a leaving groupLG, for example halogen, SCN, methoxy, preferably chlorine, at aheteroaromatic system I with a nucleophilic group IV.

1 equivalent of the compound I and 1 to 3 equivalents of a base, forexample triethylamine or ethyldiisopropylamine, are stirred in asolvent, for example 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamideor N,N-dimethylacetamide. At a temperature of −60 to 0° C., 0.8 to 1.5equivalents of a compound IV are added. The reaction mixture is stirredfor 6 to 72 h at a temperature of 15 to 75° C. Then the solvent isdistilled off and the residue is purified by chromatography.

Step 2C

The end compound V is prepared by substitution of a leaving group LG,for example halogen, SCN, methoxy, preferably chlorine, at aheteroaromatic system XI by a nucleophile II.

1 equivalent of the compound XI and 1 to 1.5 equivalents of the compoundII are stirred in a solvent, for example 1,4-dioxane,N,N-dimethyl-formamide, N,N-dimethylacetamide orN-methyl-2-pyrrolidinone. At a temperature of 15 to 40° C. 1 to 2equivalents of an acid, for example sulphuric acid or hydrochloric acid,are added. The reaction mixture is stirred for another 6 to 72 h at atemperature of 20 to 100° C. Then the solvent is distilled off and theresidue is purified by chromatography.

Chromatography:

For medium pressure chromatography (MPLC) silica gel made by Millipore(name: Granula Silica Si-60A 35-70 μm) or C-18 RP-silica gel made byMacherey Nagel (name: Polygoprep 100-50 C18) is used.

For high pressure chromatography columns made by Waters (name: XTerraPrep. MS C18, 5 μM, 30*100 mm or Symmetrie C18, 5 μm, 19*100) are used.

Nuclear Magnetic Resonance (NMR) Spectroscopy:

The measurement is carried out in deuterised dimethylsulphoxide-d6. Ifother solvents are used they are explicitly mentioned in the Examples orin the methods. The measurements are given on a delta scale in ppm.Tetramethylsilane is taken as the standard. The measurements are carriedout on an Avance 400 (400 MHz NMR spectrometer) made by Messrs BrukerBiospin GmbH.

The NMR spectra are given purely in a descriptive capacity. Basically,only the visible molecular signals are listed. If for example molecularsignals are partly or completely masked by foreign signals such as forexample water signals, DMSO signals or CDCl₃ signals they are notmentioned.

Mass Spectroscopy/UV Spectrometer:

These data are generated using an HPLC-MS apparatus (high performanceliquid chromatography with mass detector) made by Agilent.

The apparatus is constructed so that a diode array detector (G1315B madeby Agilent) and a mass detector (1100 LS-MSD SL; G1946D; Agilent) areconnected in series downstream of the chromatography apparatus (column:Zorbax SB-C8, 3.5 μm, 2.1*50, Messrs. Agilent). The apparatus isoperated with a flow of 0.6 ml/min For a separation process a gradientis run through within 3.5 min (start of gradient: 95% water and 5%acetonitrile; end of gradient: 5% water and 95% acetonitrile; in eachcase 0.1% formic acid is added to the two solvents).

Method 12-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

5 g (21.9 mmol) 2,4-dichloro-5-trifluoromethyl-pyrimidine are dissolvedin 50 ml 1,4-dioxane and combined with 5.5 g (21.9 mmol)4-amino-3-methoxybenzoic acid-propylamide hydrochloride (Zhuangyu Zhang,et al. 1989, J Pharml Sci. 78(10):829-32). 7.5 ml (43.8 mmol)ethyldiisopropylamine are added to this reaction mixture and the mixtureis stirred for 2 days at ambient temperature. Then the reaction mixtureis diluted with 250 ml of ethyl acetate and washed first with 300 mlaqueous 10% KHSO₄ solution, then with 300 ml saturated aqueous NaClsolution. The organic phase is dried with MgSO₄ and the solvent iseliminated in vacuo. The crude product is purified by columnchromatography. The carrier used is silica gel and the eluant is amixture of cyclohexane:ethyl acetate (75:25).

Yield: 2.30 g (5.9 mmol; 27%)

¹H-NMR: 0.91 (t, 3H), 1.50-1.61 (m, 2H), 3.20-3.28 (m, 2H), 3.87 (s,3H), 7.46-7.51 (m, 1H), 7.52-7.56 (m, 1H), 7.70-7.75 (m, 1H), 8.44 (t,1H), 8.75 (s, 1H), 9.73 (s, 1H)

Method 2 7-amino-2,3-dihydro-isoindol-1-one

a) 7-nitro-2,3-dihydro-isoindol-1-one

1.5 g (5.473 mmol) methyl 2-bromomethyl-6-nitro-benzoate are dissolvedin 20 ml N,N-dimethylformamide and combined with 15 ml of methanolicammonia (7 mmol/ml). After 20 h at 25° C. the mixture is diluted with100 ml of ethyl acetate and extracted 3 times with saturated sodiumhydrogen carbonate solution. The organic phase is dried with magnesiumsulphate and the solvent is eliminated in vacuo.

Yield: 960 mg (5.389 mmol, 99%)

MS-ESI+: m/z=179 [M+H]⁺

b) 7-amino-2,3-dihydro-isoindol-1-one

960 mg (5.389 mmol) 7-nitro-2,3-dihydro-isoindol-1-one are dissolved in100 ml of tetrahydrofuran and combined with 100 mg palladium oncharcoal. Then the mixture is stirred for 20 h at 25° C. and 4 barhydrogen pressure (H₂ pressure). The catalyst is filtered off and thesolvent is eliminated in vacuo.

Yield: 734 mg (4.958 mmol, 92%)

MS-ESI+: m/z=149 [M+H]⁺

The following 7-amino-2,3-dihydro-isoindol-1-one derivatives areprepared analogously to this method. A corresponding amine is usedinstead of ammonia:

MS (ESI) (M + H)⁺

163

177

191

231

219

233

207

234

274

195

213

231

209

245

188

187

206

233

233

202

206

191

205

227

223

193

225

243

221

255

192

255

178

192

211/213

247

247

261

261

261

261

223

223

221

247

246

235

224

222

Method 3 Ethyl (4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate

a) ethyl (4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate

500 mg (3.1 mmol) 4-amino-isobenzofuran-1,3-dione and 1.13 g (3.1 mmol)(ethoxy-carbonylmethylene)-triphenylphosphorane are dissolved in 5 ml oftetrahydrofuran (THF) and refluxed for 3 h. Then the solvent iseliminated in vacuo. The crude product is purified by columnchromatography. The carrier used is silica gel and the eluant used is amixture of cyclohexane:ethyl acetate (75:25).

Yield: 221 mg (0.95 mmol, 31%)

MS-ESI+: m/z=234 [M+H]⁺

b) ethyl (4-amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetate

120 mg (0.51 mmol) ethyl(4-amino-3-oxo-3H-isobenzofuran-1-ylidene)-acetate are dissolved in 50ml of methanol and combined with 50 mg palladium on activated charcoal(10% Pd). The reaction mixture is hydrogenated for 3 h at 2 bar H₂pressure and 25° C. Then the catalyst is filtered off and the solvent iseliminated in vacuo.

Yield: 116 mg (0.49 mmol, 97%)

MS (ESI): m/z=236 (M+H)⁺

¹H-NMR: 1.17 (t, 3H), 2.68-2.78 (m, 1H), 3.08-3.16 (m, 1H), 4.10 (q,2H), 5.67-5.74 (m, 1H), 6.28 (bs, 2H), 6.61-6.70 (m, 2H), 7.30-7.38 (m,1H)

Method 4 5-amino-3H-quinazolin-4-one

a) 2,6-diaminobenzamide

5 g (25.373 mmol) 2,6-dinitro-benzonitrile is combined with 20 ml of anaqueous 80% sulphuric acid and stiffed for 2 h at 80° C. The reactionmixture is combined with 100 ml of tetrahydrofuran and neutralised with10% aqueous sodium hydroxide solution. The organic phase is separatedoff, combined with another 100 ml of tetrahydrofuran and 200 mgpalladium on charcoal and stirred for 20 h at 8 bar H₂ pressure and 25°C. The solids are filtered off. The filtrate is combined with 300 ml ofethyl acetate and extracted with saturated potassium hydrogen carbonatesolution. The organic phase is separated off, dried and the solvent iseliminated in vacuo. The residue is purified by chromatography. Thecarrier used is silica gel and the eluant used is dichloromethane, towhich 7% of a mixture of 90% methanol and 10% saturated aqueous ammoniasolution are added.

Yield: 900 mg (5.958 mmol; 23%)

MS (ESI): 152 (M+H)⁺

b) 5-amino-3H-quinazolin-4-one

900 mg (5.958 mmol) 2,6-diaminobenzamide are dissolved in 3.6 mlN,N-dimethylacetamide and combined with 6.3 ml (57.01 mmol)trimethylorthoformate and 792 μl (8.865 mmol) 98% sulphuric acid. After16 h at 25° C. the reaction mixture is taken up with 20 ml of methanoland the solvent is eliminated in vacuo. The residue is again taken up in20 ml of methanol, neutralised with concentrated ammonia. The solvent iseliminated in vacuo and the residue purified by chromatography. Thecarrier used is silica gel and the eluant used is dichloromethane, towhich 7% of a mixture of 90% methanol and 10% saturated aqueous ammoniasolution are added.

Yield: 782 mg (4.852 mmol; 81%)

MS (ESI): 162 (M+H)⁺

Method 5 9-amino-2,3,4,5-tetrahydro-2-benzazepin-1-one

500 mg (1.825 mmol) 2-bromomethyl-6-nitro-methylbenzoate are heated to100° C. in 2 ml trimethyl phosphate for 5 h.2-(dimethylphosphonomethyl)-6-nitromethylbenzoate is obtained byevaporation under a high vacuum and used further directly. The crudeproduct is dissolved in 24 ml of tetrahydrofuran at −70° C. under N₂,2.7 ml (2.7 mmol) of a 1 M lithium hexamethyldisilazide solution intetrahydrofuran is added dropwise and then 430 mg (2.70 mmol)tert.-butyl-N-(2-oxoethyl)-carbamate in 5 ml of tetrahydrofuran areadded. The reaction mixture is slowly heated to ambient temperature,combined with 5 ml of 1 M HCl and extracted with ethyl acetate. Thecombined organic phases are concentrated by evaporation and, bychromatography on silica gel with a mixture of cyclohexane-ethyl acetatein the ratio 95:5 to 75:25, 338 mg (1.006 mmol, 55%) of the E-/Z mixtureof 2-(3-tert.-butoxycarbonylamino-prop-1-en-1-yl)-6-nitro-methylbenzoateare obtained. This E-/Z-mixture is treated for 12 h with 10 ml of asaturated methanolic potassium hydroxide solution. After acidificationwith aqueous 1 M HCl and extraction with ethyl acetate 302 mg (0.938mmol, 93%) of the E-/Z mixture of2-(3-tert.-butoxycarbonylamino-prop-1-en-1-yl)-6-nitro-methylbenzoicacid are obtained. To this are added 20 mg Raney nickel in 100 ml ofmethanol and the mixture is hydrogenated at 5 bar H₂ pressure. Thecatalyst is filtered off, the filtrate concentrated by evaporation andstirred overnight with a 1:1 mixture of trifluoroacetic acid anddichloromethane at ambient temperature. After elimination of the solvent133 mg (0.686 mmol, 73%) 2-amino-6-(3-amino-propyl)-benzoic acid areobtained. The further reaction is carried out by dissolving in 10 ml THFand 10 ml DCM with the addition of 300 mg (1.570 mmol)N-(3-dimethylaminopropyl)-N⁴-ethylcarbodiimide hydrochloride and 134 μl(0.830 mmol) N,N-diisopropyl-ethylamine and 48 h stirring at ambienttemperature. The solvent is eliminated in vacuo and the crude product ispurified by chromatography with C18-RP silica gel and an eluant mixtureof acetonitrile and water in the ratio 5:95 to 95:5, to which 0.1%formic acid has been added.

Yield: 28 mg (0.160 mmol, 23%)

MS (ESI): m/z=177 (M+H)⁺

Method 6 4-amino-1-methyl-1,2-dihydro-indazol-3-one

a) 4-nitro-1,2-dihydro-indazol-3-one

5 g (27.5 mmol) 2-amino-6-nitro-benzoic acid are combined with 22.2 ml(225.3 mmol) concentrated HCl and 45 ml (30.0 mmol) 5% aqueous sodiumnitrite solution and stirred for 1 h at ambient temperature. Then thesuspension is diluted with 150 ml dist. H₂O and added dropwise to 350 mldestilliertes water which has been saturated with sulphur dioxide.Sulphur dioxide is piped through the reaction mixture for a further 30min. Then the reaction mixture is refluxed for 30 min and then left tocool slowly to 20° C. The resulting precipitate is filtered off.

Yield: 1.7 g (9.5 mmol, 35%)

MS (ESI): m/z=180 (M+H)⁺

b) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one

306 mg (1.7 mmol) 4-nitro-1,2-dihydro-indazol-3-one are dissolved in 1ml N,N-dimethyl-acetamide, combined with 150 μl (2.4 mmol) methyl iodideand 500 μl (2.32 mmol) of N-ethyldiisopropylamide and stiffed for 2 h atambient temperature. Then the reaction mixture is combined with 40 ml ofa 1 N aqueous hydrochloric acid and extracted twice with 50 mldichloromethane. Then the organic phase is dried with MgSO₄, the solventis eliminated in vacuo and the crude product is purified bychromatography. The carrier used is C18-RP-silica gel and a gradient isrun through which consists of 95% water and 5% acetonitrile at thestarting point and 5% water and 95% acetonitrileat the finishing point.

Yield: 144 mg (0.7 mmol, 44%)

MS (ESI): m/z=194 (M+H)⁺

¹H-NMR: 3.90 (s, 3H), 7.47-7.52 (m, 1H), 7.68-7.73 (m, 1H), 7.88-7.93(m, 1H), 10.53 (s, 1H)

c) 4-amino-1-methyl-1,2-dihydro-indazol-3-one

140 mg (0.7 mmol) 1-methyl-4-nitro-1,2-dihydro-indazol-3-one aresuspended in 6 ml of ethanol and combined with 600 mg (4.4 eq, 2.9 mmol)sodium dithionite, dissolved in 2 ml distilled water, and stirred for 15min at 25° C. Then the reaction mixture is combined with distilled waterand extracted twice with ethyl acetate. Then the organic phase is driedwith MgSO₄ and the solvent is eliminated in vacuo.

Yield: 33 mg (0.2 mmol, 28%)

MS (ESI): m/z=164 (M+H)⁺

4-amino-1,2-dihydro-indazol-3-one and the following compounds areprepared analogously to this method.

MS (ESI) (M + H)⁺

178

194

178

Method 7 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one

a) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate

400 mg (1.8 mmol) methyl 2-cyanomethyl-6-nitro-benzoate are dissolved in13 ml THF, combined with 114 μl (1.8 mmol) methyl iodide and the mixtureis cooled to −20° C. under a nitrogen atmosphere. Then at thistemperature 250 mg (2.2 mmol) potassium-tert-butoxide are added. After 1h the solvent is eliminated in vacuo and the crude product is purifiedby chromatography. The carrier used is C18-RP-silica gel and a gradientis run through which consists of 95% water and 5% acetonitrile at thestarting point and 5% water and 95% acetonitrile at the finishing point.

Yield: 289 mg (1.2 mmol, 68%)

MS (ESI): 233 (M−H)⁻

b) 8-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one

400 mg (1.8 mmol) methyl 2-(cyanomethyl-2-methyl)-6-nitro-benzoate aredissolved in 13 ml of methanol and combined with 50 mg Raney nickel. Thereaction mixture is hydrogenated for 16 h at 4 bar H₂ pressure and 25°C. Then the catalyst is filtered off and the solvent is eliminated invacuo.

Yield: 170 mg (0.8 mmol, 46%)

MS (ESI): 177 (M+H)⁺

8-amino-3,4-dihydro-2H-isoquinolin-1-one and8-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one and the followingcompounds are prepared analogously to this method.

MS (ESI) (M + H)⁺

221

253

205

Method 8 7-amino-indan-1-one

a) indan-4-ylamine

24 ml (349 mmol) 65% nitric acid are cooled to 0-5° C. 28 ml (518.5mmol) of concentrated sulphuric acid are slowly added dropwise whilecooling with ice. This solution is cooled to 5° C. and slowly addeddropwise to 30 ml (232 mmol) indane cooled to 0-5° C., with vigorousstirring and further cooling with ice. The reaction mixture is stirredfor 30 min at 0-5° C., and then heated to 25° C. for 1 h with stirring.Then the solution is added dropwise to 150 ml ice/water and stirred for30 min The aqueous phase is extracted three times with 200 ml diethylether. The combined organic phases are washed twice with 200 mlsaturated sodium hydrogen carbonate solution and once with 150 mldistilled water. Then the organic phase is dried with MgSO₄ and thesolvent is eliminated in vacuo. The crude product is dissolved in 250 mlof methanol and combined with 4.5 g Raney nickel. The reaction mixtureis hydrogenated for 16 h at 3 bar H₂ pressure and 25° C. Then thecatalyst is filtered off and the solvent is eliminated in vacuo. Thecrude product is purified by column chromatography. The carrier used issilica gel and the eluant used is a mixture of cyclohexane:ethyl acetate(75:25).

Yield: 3.81 g (28.6 mmol, 12%)

MS (ESI): 134 (M+H)⁺

¹H-NMR: 1.90-2.00 (m, 2H), 2.61 (t, 2H), 2.76 (t, 2H), 4.73 (s, 2H),6.33-6.38 (m, 1H), 6.39-6.45 (m, 1H), 6.76-6.83 (m, 1H)

b) N-indan-4-yl-acetamide

226 mg (1.7 mmol) indan-4-ylamine are combined with 5 ml aceticanhydride. The suspension is stirred for 16 h at 70° C. The resultingsolution is stirred into 40 ml distilled water, adjusted to pH 7 withsodium carbonate and extracted three times with 30 ml of ethyl acetate.Then the organic phase is dried with MgSO₄, the solvent is eliminated invacuo and the crude product is purified by chromatography. The carrierused is silica gel and the eluant used is a mixture of cyclohexane:ethylacetate (70:30).

Yield: 152 mg (0.9 mmol, 51%)

MS (ESI): 176 (M+H)⁺

¹H-NMR: 1.93-2.03 (m, 2H), 2.04 (s, 3H), 2.79 (t, 2H), 2.86 (t, 2H),6.94-7.01 (m, 1H), 7.02-7.10 (m, 1H), 7.36-7.44 (m, 1H), 9.25 (s, 1H)

c) N-(3-oxo-indan-4-yl)-acetamide

147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetoneand combined with 770 μl of a 15% aqueous magnesium sulphate solution.The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassiumpermanganate are added batchwise. After 2 h the mixture is diluted with50 ml of water, and extracted three times with 20 ml chloroform. Theorganic phase is dried with magnesium sulphate and the solvent iseliminated in vacuo and the crude product is purified by chromatography.The carrier used is silica gel and the eluant used is a mixture ofcyclohexane:ethyl acetate (85:15).

Yield: 95 mg (0.500 mmol, 60%)

MS (ESI): 190 (M+H)⁺

d) 7-amino-indan-1-on

500 mg (2.6 mmol) N-(3-oxo-indan-4-yl)-acetamide are dissolved in 5 mlof ethanol, combined with 5 ml 18% hydrochloric acid and stirred for 3 hat 70° C. Then the reaction mixture is stirred into 100 ml distilledwater, adjusted to pH 7 with sodium carbonate and extracted three timeswith 30 ml of ethyl acetate. Then the organic phase is dried withmagnesium sulphate and the solvent is eliminated in vacuo.

Yield: 388 mg (2.6 mmol, 100%)

8-amino-3,4-dihydro-2H-naphthalen-1-one is prepared analogously to thismethod. 1,2,3,4-tetrahydronaphthalene is used as starting materialinstead of indane.

Method 9 N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide

a) 2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide

870 mg (4.5 mmol) 2-amino-7-nitro-2,3-dihydro-isoindol-1-one (preparedanalogously to method 2) are dissolved in 82 ml dichloromethane and 64ml THF. The solution is combined with 2.8 ml (3.3 eq, 20 mmol)benzyloxyacetyl chloride, 4.8 ml (28.0 mmol) N-ethyldiisopropyl-amineand 10 mg N,N-dimethylaminopyridine and stirred for 3 h at 25° C. Thenthe reaction mixture is combined with 100 ml aqueous 0.1 N hydrochloricacid and extracted three times with 50 ml of ethyl acetate. The organicphase is dried with magnesium sulphate, the solvent is eliminated invacuo and the crude product is purified by chromatography. The carrierused is silica gel and the eluant used is a mixture ofdichloromethane:methanol (95:5).

Yield: 910 mg (2.7 mmol, 59%)

b) N-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide

790 mg (2.3 mmol)2-benzyloxy-N-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-acetamide aredissolved in 100 ml of methanol and combined with 80 mg palladiumhydroxide. The reaction mixture is hydrogenated for 48 h at 4 bar H₂pressure and 25° C. Then the catalyst is filtered off and the solvent iseliminated in vacuo. The crude product is purified by chromatography.The carrier used is silica gel and the eluant used is a mixture ofdichloromethane:methanol (90:10).

Yield: 210 mg (0.1 mmol, 41%)

MS (ESI): 222 (M+H)⁺

Method 10 6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one

a) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile

2.01 g (22 mmol) 1-amino-2-butanol are dissolved in 6.5 ml 1,4-dioxane,combined with 880 mg (7.8 mmol) sodium hydride and stirred for 30 min atambient temperature. 2 g (14.7 mmol) of 2-amino-6-fluorobenzonitrile areadded to this reaction mixture and it is stirred for 24 h at 50° C. Thenthe solvent is eliminated in vacuo and the crude product is purified bychromatography. The carrier used is silica gel and the eluant used isdichloromethane, to which 5% of a mixture of 90% methanol and 10%saturated aqueous ammonia solution has been added.

Yield: 1.15 g (5.6 mmol, 38%)

MS (ESI): 206 (M+H)⁺

b) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid

1.15 g (5.6 mmol) 2-amino-6-(1-aminomethyl-propoxy)-benzonitrile aredissolved in 10 ml 20% ethanolic KOH and stirred for 24 h at 80° C. Thenthe solvent is eliminated in vacuo and the crude product is purified bychromatography. The carrier used is silica gel and the eluant used isdichloromethane, to which 12% of a mixture of 90% methanol and 10%saturated aqueous ammonia solution have been added.

Yield: 262 mg (1.2 mmol, 21%)

MS (ESI): 225 (M+H)⁺

c) 6-amino-2-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one

262 mg (1.2 mmol) 2-amino-6-(1-aminomethyl-propoxy)-benzoic acid aredissolved in 26 ml THF, combined with 680 mg (3.5 mmol)1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 0.6 ml(3.5 mmol) diisopropyl-ethylamine and stirred for 3 h at 50° C. Then thesolvent is eliminated in vacuo and the crude product is purified bychromatography. The carrier used is silica gel and the eluant used isdichloromethane, to which 4% of a mixture of 90% methanol and 10%saturated aqueous ammonia solution have been added.

Yield: 50 mg (0.2 mmol, 21%)

MS (ESI): 207 (M+H)⁺

The following compounds are prepared analogously to this method.1-amino-2-butanol was replaced by a corresponding aminoalcohol or by acorresponding 1,2-diaminoethylene.

MS (ESI) (M + H)⁺

207

193

235

219

233

207

207

193

221

299

219

209

269

251

179

221

206

235

227

219

207

269

225

253

241

233

Method 116-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

a) methyl 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate

1.18 g (6.5 mmol) 2-amino-6-nitrobenzoic acid, 1.0 g (4.6 mmol)D,L-phenylalanine-methylester hydrochloride, 4.05 ml (23.2 mmol)N-ethyldiisopropylamine are combined with 2.5 ml of tetrahydrofuran.1.71 g (5.1 mmol)O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium-tetrafluoroborate areadded to this reaction mixture and it is heated for 12 h to 50° C. Thenthe solvent is eliminated in vacuo and the crude product is purified bychromatography. The carrier used is silica gel and the eluant used is amixture of cyclohexane:ethyl acetate (50:50).

Yield: 1.04 g (3.03 mmol, 65%)

MS (ESI): 344 (M+H)⁺

b) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionic acid

1.04 g (3.03 mmol) methyl2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionate are dissolved in 3ml 20% ethanolic KOH and stirred for 1.5 h at 50° C. Then the solvent iseliminated in vacuo and the crude product is purified by chromatography.The carrier used is silica gel and the eluant used is dichloromethane,to which 15% of a mixture of 90% methanol and 10% saturated aqueousammonia solution has been added.

Yield: 636 mg (1.9 mmol, 64%)

MS (ESI): 329 (M+H)⁺

¹H-NMR: 2.86-2.94 (m, 1H), 3.17 (s, 1H), 3.22-3.29 (m, 1H), 4.30-4.38(m, 1H),

6.63 (s, 2H), 6.89-6.96 (m, 1H), 6.97-7.02 (m, 1H), 7.12-7.21 (m, 2H),7.21-7.27 (m, 2H), 7.28-7.35 (m, 2H), 8.33-8.43 (m, 1H)

c) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acid

410 mg (1.25 mmol) 2-(2-amino-6-nitro-benzoylamino)-3-phenyl-propionicacid are dissolved in 50 ml of methanol and combined with 40 mgpalladium on charcoal (10% Pd). The reaction mixture is hydrogenated for9 h at 5 bar H₂ pressure and 25° C. Then the catalyst is filtered off,the solvent is eliminated in vacuo and the crude product is purified bychromatography. The carrier used is C18-RP-silica gel and a gradient isrun through which consists of 95% water and 5% acetonitrile at thestarting point and consists of 5% water and 95% acetonitrile at thefinishing point.

Yield: 88 mg (0.29 mmol, 24%)

MS (ESI): 300 (M+H)⁺

d) 6-amino-3-benzyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione

88 mg (0.3 mmol) 2-(2,6-diamino-benzoylamino)-3-phenyl-propionic acidare dissolved in 2 ml THF, combined with 143 mg (0.9 mmol)1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and 103 μl(0.6 mmol) diisopropyl-ethylamine and stirred for 17 h at 50° C. Thenthe solvent is eliminated in vacuo and the crude product is purified bychromatography. The carrier used is silica gel and the eluant used isdichloromethane, to which 5% of a mixture of 90% methanol and 10%saturated aqueous ammonia solution have been added.

Yield: 22 mg (0.08 mmol, 27%)

MS (ESI): 282 (M+H)⁺

The following compounds are prepared analogously to to method 11.

MS (ESI) (M + H)⁺

192

206

206

218

220

220

232

232

234

234

234

246

246

246

248

248

248

250

265

265

268

277

278

278

282

283

283

288

296

192

298

298

300

300

300

307

316/318

321

321

346

Method 122-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

7.36 g (44 mmol) 4-amino-3-methoxybenzoic acid are suspended in 80 ml ofan aqueous phosphate buffer solution (pH 6.3) and combined with 9.5 g(44 mmol) 2,4-dichloro-5-trifluoro-methyl-pyrimidine, which is dissolvedin 240 ml 1,4-dioxane. After 4 h at 100° C. the reaction mixture iscrystallised at 0° C. The precipitate is filtered off, the filtrate iscombined with 150 ml of ethyl acetate and washed twice with 200 ml of asaturated aqueous sodium hydrogen carbonate solution. The organic phaseis dried with MgSO₄ and the solvent is eliminated in vacuo. The crudeproduct is suspended in 10 ml n-hexane and refluxed. The precipitate isfiltered off, suspended in 48 ml of a saturated aqueous sodium hydrogencarbonate solution and heated to 65° C. for 1 h. Then the solution iscrystallised at 0° C. The precipitate is filtered off, the filtrate isacidified with 1 N aqueous hydrochloric acid and combined with 100 ml ofethyl acetate. The organic phase is separated off, dried with magnesiumsulphate and the solvent is eliminated in vacuo. The residue isrecrystallised from ethyl acetate.

Yield: 330 mg (0.95 mmol, 2%)

MS (ESI): 348 (M+H)⁺

¹H-NMR: 1.55 (s, 1H), 4.01 (s, 3H), 7.61-7.64 (m, 1H), 7.79-7.85 (m,1H), 8.34

(s, 1H), 8.59-8.63 (m, 1H), 8.66 (s, 1H)

Method 13 4-(4-amino-cyclohexyl)-morpholine

a) dibenzyl-(4-morpholino-4-yl-cyclohexyl)-amine

3.9 g (30 mmol) 4-dibenzylamino-cyclohexanone are dissolved in 100 mldichloromethane and stirred with 3.9 g (45 mmol) morpholine and 9.5 g(45 mmol) sodium triacetoxyborohydride for 12 h at ambient temperature.Then water and potassium carbonate are added, the organic phase isseparated off, dried and the solvent is eliminated in vacuo. The crudeproduct is purified by column chromatography. The carrier used is silicagel and the eluant used is ethyl acetate, to which 10% of a mixture of90% methanol and 10% saturated aqueous ammonia solution have been added.The suitable fractions are evaporated down in vacuo.

Yield: 6.6 g (18 mmol, 60%) cis-isomer

2 g (5.4 mmol, 18%) trans-isomer.

b) trans-4-morpholino-4-yl-cyclohexylamine

7.2 g (16.4 mmol) trans-dibenzyl-4-morpholino-cyclohexylamine aredissolved in 100 ml of methanol and hydrogenated on 1.4 g palladium oncharcoal (10% Pd) at 30-50° C. The solvent is eliminated in vacuo andthe residue is crystallised from ethanol and concentrated hydrochloricacid.

Yield: 3.9 g (15.2 mmol, 93%)

melting point: 312° C.

The following compounds are prepared analogously to Method 13:

MS (ESI) (M + H)⁺

169

211

213

238

Method 142-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

a)2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

2 g (9.217 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine are dissolvedin 4 ml dioxane and combined with 6.01 g (18.430 mmol) caesium carbonateand 2.16 g (7.363 mmol) benzyl 4-amino-3-methoxybenzoate (WO 9825901).This suspension is stirred for 30 h at 100° C. The suspension iscombined with 50 ml dichloromethane and methanol and filtered to removethe insoluble constituents. The solvent is eliminated in vacuo and theresidue is purified by column chromatography. The carrier used is silicagel and the eluant used is a mixture of 85% cyclohexane and 15% ethylacetate.

Yield: 1.03 g (2.360 mmol; 26%)

UV max: 320 nm

MS (ESI): 438/440 (M+H)⁺ Cl distribution

436/438 (M−H)⁻ Cl distribution

b)2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

1 g (2.284 mmol)2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidineare dissolved in 50 ml THF and combined with 100 mg palladium hydroxide.The reaction mixture is stirred for 16 h at ambient temperature and 4bar hydrogen pressure. Then the catalyst is filtered off and the solventis eliminated in vacuo.

Yield: 0.76 g (2.192 mmol; 96%)

UV max: 288 nm

MS (ESI): 346/348 (M−H)⁻Cl distribution

The following compounds are prepared analogously to this process:

-   2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

MS (ESI): 316/318 (M−H)⁻Cl distribution

-   2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine

MS (ESI): 492/494 (M+H)⁺Cl distribution

-   2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine

MS (ESI): 522/524 (M+H)⁺Cl distribution

Method 15 3-pyrrolidin-1-yl-cyclobutylamine

a) tert. butyl (3-benzyloxy-cyclobutyl)-carbamate

9.28 g (45 mmol) 3-benzyloxy-cyclobutancarboxylic acid (Org. Lett.6(11), 1853-1856, 2004) are suspended in 80 ml dry tert-butanol andcombined with 5.1 g (50 mmol) triethylamine and 13.8 g (50 mmol)phosphoric acid diphenylester azide. The reaction mixture is stirred for20 h under reflux conditions. The solvent is eliminated in vacuo and theresidue is taken up in dichloromethane. The organic phase is washedthree times with 2 N sodium hydroxide solution, dried with sodiumsulphate and the dichloromethane is eliminated in vacuo. The crudeproduct is recrystallised from acetonitrile (1 g crude product: 5 mlacetonitrile).

Yield: 5.98 g (22 mmol; 48%)

MS (ESI): 178 (M+H-boc)⁺ Boc cleaving in the mass detector

b) tert. butyl (3-hydroxy-cyclobutyl)-carbamate

2.77 g (10 mmol) tert. butyl (3-benzyloxy-cyclobutyl)-carbamate aresuspended in 100 ml of methanol and combined with 200 mg palladiumhydroxide. The reaction mixture is stirred for 5 h at 45° C. and 45 barH₂ pressure. Then the catalyst is filtered off and the solvent iseliminated in vacuo. The residue is taken up in chloroform and washedthree times with aqueous sodium hydrogen carbonate solution. The organicphase is dried with magnesium sulphate and the solvent is eliminated invacuo.

Yield: 1.53 g (8.2 mmol; 82%)

MS (ESI): 188 (M+H)⁺

c) tert. butyl (3-tosyl-cyclobutyl)-carbamate

18.7 g (100 mmol) tert. butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1g (120 mmol) triethylamine are placed in 500 ml chloroform. 20.5 g (105mmol) tosyl chloride, dissolved in 150 ml chloroform, is added dropwiseto this solution at 0° C. with stirring. Then the mixture is left tocome up to ambient temperature and stirred for 2 h. The organic phase iswashed successively with water, dilute hydrochloric acid, sodiumhydrogen carbonate solution and water. The organic phase is dried withmagnesium sulphate and the solvent is eliminated in vacuo.

Yield: 28.30 g (83 mmol; 83%)

MS (ESI): 342 (M+H)⁺

d) tert. butyl (3-pyrrolidine-cyclobutyl)-carbamate

34.1 g (100 mmol) tert. butyl (3-tosyl-cyclobutyl)-carbamate aredissolved in 750 ml pyrrolidine, and combined with a catalytic amount ofDMAP. The reaction mixture is refluxed for 20 h with stirring. Thepyrrolidine is eliminated in vacuo, the residue is taken up in 500 ml ofethyl acetate and washed twice with saturated sodium hydrogen carbonatesolution. The organic phase is dried with magnesium sulphate and thesolvent is eliminated in vacuo. The crude product consists—as in all theanalogous reactions—of a mixture of 2 isomeric compounds which areseparated by column chromatography. The stationary phase used is silicagel and the eluant used is dichloromethane, to which 9% of a mixture of90% methanol and 10% saturated aqueous ammonia solution have been added.

The substances that elute first are designated as follows:

Yield product A: 1 g (4.17 mmol; 4%)

RF value (silica gel; dichloromethane:methanol:conc. aqueousammonia=90:9:1)=0.62

The substances that elute second are designated as follows:

Yield product C, 2.00 g (8.33 mmol; 8%)

RF value (silica gel; dichloromethane:methanol:conc. aqueousammonia=90:9:1)=0.53

e) (*1′,*1″)-3-pyrrolidin-1-yl-cyclobutylamine

1 g (4.17 mmol) tert. butyl (3-pyrrolidine-cyclobutyl)-carbamate(product A from precursor) are stiffed in 20 ml of a 2 N aqueoushydrochloric acid solution for 2 h at 40° C. Then the solvent iseliminated in vacuo and the residue is recrystallised from ethanol.

Yield: 0.43 g (2.786 mmol; 67%)

MS (ESI): 141 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

170

210

184

224

171

212

143

198

196

194

183

(*2′,*2″)-3-pyrrolidin-1-yl-cyclobutylamine

1 g (4.17 mmol) tert. butyl (3-pyrrolidine-cyclobutyl)-carbamate(product C from precursor) are stiffed in 20 ml of a 2 N aqueoushydrochloric acid solution for 2 h at 40° C. Then the solvent iseliminated in vacuo and the residue is recrystallised from ethanol.

Yield: 0.43 g (3.09 mmol; 74%)

MS (ESI): 141 (M+H)⁺

The following compounds are prepared analogously to this method:

MS (ESI) (M + H)⁺

155

157

171

184

170

210

253

224

183

212

143

141

198

251

194

196

171

Method 162-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

1 g (3.15 mmol)2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine aredissolved in 5 ml DMF and combined batchwise with 3.36 g (18.89 mmol)N-bromosuccinimide. The reaction mixture is stirred for 16 h at ambienttemperature. The solvent is eliminated in vacuo and the residue ispurified by column chromatography. The carrier used is C18-RP-silica geland a gradient is run through which consists of 95% water and 5%acetonitrile at the starting point and consists of 2% water and 98%acetonitrile at the finishing point. 0.1% formic acid is added in eachcase to both the water and to the acetonitrile.

Yield: 0.57 g (1.44 mmol; 46%)

MS (ESI): 396/398 (M−H)⁺Cl/Br distribution

Method 17 5-amino-3-(2-fluoro-ethyl)-3H-quinazolin-4-one

500 mg (3.102 mmol) 5-amino-3H-quinazolin-4-one are combined with 2 ml(15.596 mmol) 1-bromo-2-fluoroethane. 125 mg (3.125 mmol) sodium hydrideare added thereto and the mixture is stirred for 5 days at ambienttemperature. The reaction mixture is diluted with 100 ml of ethylacetate and washed with 100 ml saturated aqueous sodium chloridesolution. The aqueous phase is combined with 50 ml 1 N sodium hydroxidesolution and extracted 5 times with ethyl acetate. The combined organicphases are dried and the solvent is eliminated in vacuo. The residue ispurified by column chromatography. The carrier used is C18-RP-silica geland a gradient is run through which consists of 95% water and 5%acetonitrile at the starting point and consists of 5% water and 95%acetonitrile at the finishing point. 0.1% formic acid is added in eachcase to both the water and to the acetonitrile.

Yield: 67 mg (0.323 mmol; 10%)

MS (ESI): 208 (M+H)⁺

Method 18 8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one

a) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one

1.466 g (9.039 mmol) 8-amino-3,4-dihydro-2H-isoquinolin-1-one aredissolved in 15 ml DMF and combined with 3.226 g (23.340 mmol) potassiumcarbonate and with 3.808 ml (31.420 mmol) benzylbromide. This reactionmixture is stirred for 16 h at 50° C. The reaction mixture is dilutedwith ethyl acetate and extracted with sodium hydrogen carbonatesolution. The organic phases are dried and the solvent is eliminated invacuo.

Yield: 1.670 g (4.877 mmol; 54%)

MS (ESI): 343 (M+H)⁺

b) 8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one

1.06 g (3.095 mmol) 8-dibenzylamino-3,4-dihydro-2H-isoquinolin-1-one arecombined with 1.5 ml (12 mmol) 1-bromo-2-fluoro-ethane and at ambienttemperature 780 mg (19.50 mmol) sodium hydride are added batchwise overa period of 30 h. The reaction mixture is diluted with ethyl acetate andextracted with sodium hydrogen carbonate solution. The organic phasesare dried and the solvent is eliminated in vacuo. The crude product ispurified by column chromatography. The carrier used is silica gel andthe eluant used is dichloromethane, to which 5% of a mixture of 90%methanol and 10% saturated aqueous ammonia solution have been added.

Yield: 0.83 g (2.136 mmol; 69%)

MS (ESI): 389 (M+H)⁺

c) 8-amino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one

830 mg (2.136 mmol)8-dibenzylamino-2-(2-fluoro-ethyl)-3,4-dihydro-2H-isoquinolin-1-one aredissolved in 50 ml of methanol and combined with 80 mg palladiumhydroxide. The reaction mixture is stirred for 48 h at ambienttemperature and 4.5 bar H₂ pressure. Then the catalyst is filtered offand the solvent is eliminated in vacuo.

Yield: 0.403 g (1.935 mmol; 91%)

MS (ESI): 209 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

177

191

223

Method 19 7-amino-5H-phenanthridin-6-one

250 mg (1.16 mmol) methyl 2-chloro-6-nitro-benzoate, 458 mg (1.392 mmol)caesium carbonate, 211 mg (1.218 mmol) 2-nitrophenylboric acid and 18 mg(0.035 mmol) bis(tri-tert-butylphosphin)palladium(0) are placed underargon and combined with 0.8 ml dioxane. This reaction mixture is stirredfor 48 h at 80° C. The reaction mixture is diluted with ethyl acetateand extracted with 1 N hydrochloric acid. The organic phase is dried andthe solvent is eliminated in vacuo. The crude product is purified bycolumn chromatography. The carrier used is C18-RP-silica gel and agradient is run through which consists of 95% water and 5% acetonitrileat the starting point and consists of 5% water and 95% acetonitrile atthe finishing point. 0.1% formic acid is added to both the water and theacetonitrile. The suitable fractions are freeze-dried. 71 mg of theintermediate product thus obtained are dissolved in 50 ml of methanoland combined with 10 mg palladium on charcoal. The reaction mixture isstirred for 48 h at ambient temperature and 4.5 bar H₂ pressure. 50 mldichloromethane are added to the reaction solution, the mixture istreated for 5 min in the ultrasound bath and then the catalyst isfiltered off. The solvent is eliminated in vacuo.

Yield: 46 mg (0.221 mmol; 94%)

MS (ESI): 211 (M+H)⁺

Method 20 C-(5-morpholin-4-ylmethyl-1H-[1,2,3]triazol-4-yl)-methylamine

18.021 g (100 mmol) 1-azido-4-morpholino-2-butyne and 19.728 g (100mmol) dibenzylamine are dissolved in 100 ml dioxane and heated to 80° C.with stiffing. After stirring for 20 h at this temperature the solventis eliminated in vacuo and the residue is purified by columnchromatography. The carrier used is silica gel and the eluant used isdichloromethane, to which 5% of a mixture of 90% methanol and 10%saturated aqueous ammonia solution have been added. The suitablefractions are combined and the solvent is eliminated in vacuo. Theresidue is dissolved in 480 ml of methanol and combined with 30 mlconcentrated aqueous hydrochloric acid and 1 g palladium on charcoal.This reaction mixture is stiffed for 5 h at 50° C. and 50 bar H₂pressure. Then the catalyst is filtered off and the solvent iseliminated in vacuo.

Yield: 8.588 g (28.00 mmol; 28%)

MS (ESI): 198 (M+H)⁺

Method 21 4-morpholin-4-ylmethyl-cyclohexylamine

2.5 g (11 mmol) tert. butyl trans-(4-formyl-cyclohexyl)-carbamatedissolved in 25 ml dimethylacetamide are combined with 1 ml (11 mmol)morpholine and 0.7 ml acetic acid. 2.4 g (11.3 mmol) sodiumtriacetoxyborohydride dissolved in 12.5 ml dimethylacetamide is added tothis mixture. The reaction mixture is stirred for 16 h at ambienttemperature. Then the reaction mixture is added to 250 ml 10% potassiumhydrogen carbonate solution and this mixture is extracted three timeswith 100 ml of ethyl acetate. The organic phases are combined, dried andthen the solvent is eliminated in vacuo. The residue is taken up in 20ml dichloromethane and 20 ml trifluoroacetic acid and stirred for 1 h atambient temperature. The solvents are eliminated in vacuo.

Yield: 4.22 g (9.9 mmol; 90%) (double trifluoroacetic acid salt)

MS (ESI): 199 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

157

183

157

169

Method 22 7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one

10 g (42.157 mmol) methyl 2-acetyl-6-nitro-benzoate (J. Org. Chem.(1952), 17, 164-76), 6.06 g (54.804 mmol) 2-fluoroethylamine and 9.32 ml(54.804 mmol) N-ethyldiisopropylamine are suspended in 25 ml of tolueneand refluxed for 40 h with stirring. The reaction mixture is dilutedwith 400 ml of methanol and combined with 2.5 g palladium on charcoal.Then the mixture is stirred for 48 h at ambient temperature and 5 bar H₂pressure. The catalyst is filtered off and the solvent is eliminated invacuo. The residue is taken up in dichloromethane and washed with water.The organic phase is dried with magnesium sulphate, the solvent iseliminated in vacuo and the crude product is purified by chromatography.The carrier used is silica gel and the eluant used is a mixture ofcyclohexane:ethyl acetate (70:30).

Yield: 3.83 g (18.404 mmol, 43%)

MS (ESI): 209 (M+H)⁺

UV max: 318 nm

The following compounds are prepared analogously to this process, usingthe corresponding methyl 6-nitro-benzoate derivative:

MS (ESI) (M + H)⁺

163

177

203

207

217

221

227

241

223

225

239

253

252

278

237

245

Method 23 2-azetidin-1-yl-ethylamine

500 μl (7.49 mmol) azetidin are dissolved in 15 ml acetonitrile,combined with 4.831 g (34.822 mmol) potassium carbonate and 445 μl(7.038 mmol) chloroacetonitrile. This reaction mixture is stirred for 20h at ambient temperature. To this reaction mixture are added 20 mldiethyl ether, the suspension is stirred for 10 min and filtered toseparate the solid constituents. The filtrate is freed from solvents invacuo. 463 mg (4.816 mmol) of this intermediate product are dissolved in50 ml 7 N methanolic ammonia and Raney nickel is added. The reactionmixture is stirred for 2 h at 60° C. and 20 bar H₂ pressure. Thecatalyst is filtered off and the solvent is eliminated in vacuo.

Yield: 365 mg (3.664 mmol, 48%)

MS (ESI): 101 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

129

131

158

159

159

141

165

172

156

157

143

145

145

158

198

145

Method 24 ((S)-3-amino-pyrrolidin-1-yl)-acetonitrile

1 g (5.369 mmol) (S)-3-(Boc-amino)-pyrrolidine are dissolved in 20 mlacetonitrile and combined with 4.831 g (34.822 mmol) potassium carbonateand 322 μl (5.101 mmol) chloroacetonitrile. This reaction mixture isstirred for 20 h at ambient temperature. 20 ml diethyl ether are addedto this reaction mixture, the suspension is stirred for 10 min andfiltered to separate off the solid constituents. The filtrate is freedfrom the solvents in vacuo. The intermediate product is dissolved in 2ml dioxane and combined with 13 ml of 4 N dioxanic hydrochloric acid andstirred overnight at RT. Then the solvent is eliminated in vacuo.

Yield: 500 mg (3.995 mmol, 74%)

MS (ESI): 126 (M+H)⁺

Method 25 (R)-2-pyrrolidin-1-yl-propylamine

a) (R)-2-pyrrolidin-1-yl-propionamide

2 g (16.055 mmol) R-alaninamide hydrochloride, 6.67 g (16.083 mmol)potassium carbonate and 8 mg (0.048 mmol) potassium iodide are suspendedin 50 ml acetonitrile and then combined with 1.921 ml (16.083 mmol)1,4-dibromobutane. This reaction mixture is refluxed for 14 h withstirring. 100 ml 1 N hydrochloric acid and 100 ml dichloromethane areadded to the reaction mixture. The organic phase is separated off anddiscarded. The aqueous phase is made basic with sodium hydroxidesolution and extracted three times with dichloromethane. The organicphases are combined, dried and freed from the solvent in vacuo.

Yield: 1.305 g (9.177 mmol, 57%)

MS (ESI): 143 (M+H)⁺

b) (R)-2-pyrrolidin-1-yl-propylamine

Under a nitrogen atmosphere 31.65 ml 1 M Lithiumaluminiumhydrid solution(THF) are taken and combined with 1 g (7.032 mmol)(R)-2-pyrrolidin-1-yl-propionamide, dissolved in 2 ml THF, at 0° C. Thereaction mixture is stirred for 48 h at 50° C. The reaction mixture iscombined with 100 ml of methanol and then with the same amount ofdichloromethane while cooling with ice. Approx. 25 g silica gel areadded to this mixture and the solvent is eliminated in vacuo. Thissilica gel applied to a suction filter which has previously been chargedwith approx. 75 g silica gel. The suction filter is washed batchwisewith a total of 500 ml of a mixture of dichloromethane, methanol andaqueous conc. ammonia (90:9:1). The majority of the solvent iseliminated at a vacuum of 200 mbar and a sump temperature of approx. 50°C. The product is distilled at 69-71° C. and 10 mbar.

Yield: 160 mg (1.248 mmol, 18%)

MS (ESI): 129 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

129

129

129

143

157

157

169

183

183

197

Method 262-chloro-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

1.1 g (5.07 mmol) 2,4-dichloro-5-trifluoromethylpyrimidin are dissolvedin 1 ml dioxane and combined with 0.9 g (4.322 mmol)7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method22) and 0.9 ml (5.257 mmol) diisopropyethylamine. This mixture isstirred for 1 h at 80° C. Then the solvent is eliminated in vacuo. Thecrude product is purified by column chromatography. The carrier used isC18-RP-silica gel and a gradient is run through which consists of 95%water and 5% acetonitrile at the starting point and consists of 20%water and 80% acetonitrile at the finishing point. 0.1% formic acid areadded to both the water and to the acetonitrile. The suitable fractionsare combined with dichloromethane, the organic phase is separated off,dried and the solvent is eliminated in vacuo.

Yield: 485 mg (1.250 mmol, 25%)

MS (ESI): 389/391 (M+H)⁺; Cl distribution

The following compounds are prepared analogously to this process. Theaniline derivatives used are described in the supplements to method 2,in method 10 and in the supplements to method 10. The preparation of the2,4-dichloropyrimidine derivatives is known from the literature or maybe carried out by methods known from the literature.

MS (ESI) (M + H)⁺

363/365

367/369

349/351

381/383

333/335

373/375

447/449

355/357

399/401

366/368

345/347

385/387

381/383

Method 27 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol

a) 3-methoxy-4-nitro-benzonitrile

25 g (150.504 mmol) 3-fluoro-4-nitrobenzonitrile and 25 g (462.757 mmol)sodium methoxide are dissolved in 125 ml THF at 0° C. This reactionmixture is stirred for 30 min. The reaction mixture is extracted withethyl acetate and 1 N hydrochloric acid. The organic phase is dried withmagnesium sulphate and the solvent is eliminated in vacuo.

Yield: 25.092 g (140.852 mmol, 94%)

UV max: 334 nm

b) 3-methoxy-4-nitro-benzamidine

99 ml (99 mmol) lithium-bis-trimethylsilylamide solution (1 mol/l inTHF) are diluted with 640 ml THF, cooled to 10° C. and combined with 8.3g (46.591 mmol) 3-methoxy-4-nitro-benzonitrile. The reaction mixture isstirred for 10 min at 20° C. The mixture is cooled to 0° C. and combinedwith 80 ml 3 N hydrochloric acid. The reaction mixture is evaporateddown in vacuo and extracted with water and ethyl acetate. The aqueousphase is adjusted to pH 14 with 3 N sodium hydroxide solution.

The product is then suction filtered.

Yield: 14.30 g (crude product: 60% purity)

MS (ESI): 196 (M+H)⁺

UV max: 334 nm

c) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]acetic acid

7 g (60% purity, 21.519 mmol) 3-methoxy-4-nitro-benzamidine aredissolved in methanol and combined with 11 ml (44 mmol) 4 N dioxanichydrochloric acid, the solvents are eliminated in vacuo. The residue and6.13 g (44.384 mmol) potassium carbonate are suspended in 350 mlacetonitrile and combined with 3.24 ml (22.764 mmol) ethyl4-chloracetoacetate and 880 mg (5.301 mmol) potassium iodide. Thereaction mixture is stirred for 16 h at 45° C. The reaction mixture isdiluted with water and combined with 1 N sodium hydroxide solution, andextracted with ethyl acetate. The aqueous phase is adjusted to pH 1 with1 N HCL and saturated with sodium chloride. The product is then suctionfiltered.

Yield: 1.45 g (5.230 mmol, 24%)

MS (ESI): 278 (M+H)⁺

UV max: 294 nm

d) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol

1.45 g (5.23 mmol) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]aceticacid are dissolved in 36 ml THF and cooled to 0° C. and combined with 10ml (18 mmol) borane-THF complex (1.8 mol/l). After 1 h the mixture isheated to 20° C. and stirred for 16 h. Water is added until thedevelopment of gas has ended. Then the mixture is extracted twice withsaturated aqueous sodium hydrogen carbonate solution and ethyl acetate.The organic phases are combined, dried and freed from the solvent invacuo.

Yield: 0.65 g (2.465 mmol, 47%)

MS (ESI): 264 (M+H)⁺

UV max: 298 nm

e) 2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol

0.144 g (0.547 mmol)2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol are dissolvedin 100 ml of methanol and combined with 0.08 g (5%) palladium oncharcoal. The reaction mixture is hydrogenated for 16 h at 20° C. and 4bar H₂ pressure. The palladium on charcoal is suction filtered and themethanol is eliminated in vacuo.

Yield: 87 mg (0.373 mmol, 68%)

MS (APCI): 234 (M+H)⁺

UV max: 314 nm

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

220

251

190

2-[2-(4-amino-3-methoxy-phenyl)-thiazole-5-yl]-ethanol is preparedanalogously to the processes described above. For the cyclisation,4-amino-3-methoxy-thiobenzamide is used (analogously to J. Am. Soc. 82,2656, 1960) instead of 3-methoxy-4-nitro-benzamidine.

MS (ESI): 251 (M+H)⁺

Method 28 2-methoxy-N⁴-(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine

a) (3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine

1 g (5.884 mmol) 4-fluoro-2-methoxy-1-nitro-benzene, 975 mg (7.369 mmol)1-(3-aminopropyl)pyrrolidine and 1.5 ml (8.765 mmol)diisopropyethylamine are dissolved in 5 ml dioxane and stirred for 24 hat 95° C. The solvents are eliminated in vacuo and the crude product ispurified by column chromatography. The carrier used is silica gel andthe eluant used is dichloromethane, to which 15% of a mixture of 90%methanol and 10% saturated aqueous ammonia solution has been added.

Yield: 1.07 g (3.827 mmol; 65%)

MS (ESI): 280 (M+H)⁺

b) 2-methoxy-N⁴-(3-pyrrolidin-1-yl-propyl)-benzene-1,4-diamine

200 mg (0.716 mmol)(3-methoxy-4-nitro-phenyl)-(3-pyrrolidin-1-yl-propyl)-amine aredissolved in 10 ml of methanol and combined with 537 μl (2.148 mmol)dioxanic hydrochloric acid and 20 mg palladium on charcoal. The reactionmixture is stirred for 1 h at ambient temperature and 5 bar H₂ pressure.The catalyst is filtered off and the solvent is eliminated in vacuo.

Yield: 213 mg (0.661 mmol, 92%)

MS (ESI): 250 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

236

307

333

333

347

333

240

240

222

208

262

222

236

168

250

250

307

307

Method 292-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine

1 g (3.148 mmol)2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine(method 12 or 14) are dissolved in 5 ml DMF and combined batchwise with3.36 g (18.889 mmol) N-bromosuccinimide. This reaction mixture isstirred for 16 h at ambient temperature. Then the solvent is eliminatedin vacuo and the residue is purified by column chromatography. Thecarrier used is C18-RP-silica gel and a gradient is run through whichconsists of 95% water and 5% acetonitrile at the starting point andconsists of 2% water and 98% acetonitrile at the finishing point. 0.1%formic acid are added to both the water and to the acetonitrile.

Yield: 571 mg (1.440 mmol, 46%)

MS (ESI): 396/398 (M+H)⁺

Method 302-(4-Acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

a)4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

1 g (1.925 mmol)2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine(prepared analogously to Example 53) are dissolved in 2 ml of tolueneand combined successively with 0.43 ml (2.503 mmol)diisopropylethylamine, with 1.8 ml tert-butanol and with 0.49 ml (2.310mmol) diphenylphosphorylazide and heated to 80° C. for 18 h. Thereaction mixture is cooled, diluted with 100 ml of ethyl acetate andwashed twice with 0.5 N sodium hydroxide solution. The organic phase isdried with magnesium sulphate and the solvent is eliminated in vacuo.The residue is taken up in dichloromethane and combined with 4 Mdioxanic hydrochloric acid. The mixture is stirred for 72 h at ambienttemperature. It is diluted with ethyl acetate and extracted 4 times with1 N hydrochloric acid. The aqueous phases are combined and extractedonce with ethyl acetate. The aqueous phase is made basic with sodiumhydroxide solution and extracted three times with ethyl acetate. Theorganic phases are combined, dried and the solvent is eliminated invacuo.

Yield: 606 mg (1.236 mmol, 64%)

MS (ESI): 491 (M+H)⁺

b)2-(4-Acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

311 mg (0.634 mmol)2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineare dissolved in 10 ml THF and combined with 115 μl (0.824 mmol)triethylamine and 62 μl (0.761 mmol) acrylic chloride. This mixture isstirred for 1 h at ambient temperature. Then it is diluted with ethylacetate and extracted three times with water. The organic phase is driedwith magnesium sulphate and the solvent is eliminated in vacuo.

Yield: 340 mg (0.625 mmol, 98%)

MS (ESI): 545 (M+H)⁺

The following compounds are Prepared analogously to this Process:

MS (ESI) (M + H)⁺

581

582

659

611

Method 31 Separation of the racemic7-amino-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-one (method22) into the two enantiomers

The separation is carried out by preparative chromatography under thefollowing conditions:

column: 280×110 mm CHIRALPAK® AD 20 μm

Eluant: 95% acetonitrile/5% isopropanol (v/v)

Flow rate: 570 ml/min

Temperature: ambient temperature

The enantiomer that elutes first is known as enantiomer 1 and in thechemical formula bears the symbol *1:

Enantiomer 1

The enantiomer that elutes second is known as enantiomer 2 and in thechemical formula bears the symbol *2:

Enantiomer 2

Method 32 7-amino-3-ethyl-indan-1-one

262 mg (1.364 mmol) copper iodide are taken and heated in an argoncurrent. Then the copper iodide is suspended in ether and cooled to −78°C. At this temperature 0.8 ml of a 3 Methylmagnesium bromide solution(in ether) are added and the mixture is stirred for 10 min and then leftto thaw to 0° C. After 15 min stirring at this temperature the mixtureis cooled to −78° C. again and 200 mg (0.802 mmol)N-(3-oxo-3H-inden-4-yl)-benzamide, dissolved in 9 ml THF, are addeddropwise and the mixture is stirred for 1 h at 0° C. The reactionmixture is diluted with dichloromethane and washed three times withconcentrated aqueous ammonia solution. The organic phase is dried withmagnesium sulphate and the solvent is eliminated in vacuo. The residueis purified by column chromatography. The carrier used is C18-RP-silicagel and a gradient is run through which consists of 98% water and 2%acetonitrile at the starting point and 2% water and 98% acetonitrile atthe finishing point. 0.1% formic acid are added to both the water and tothe acetonitrile. The suitable fractions are freeze-dried. Thisintermediate product is dissolved in 2 ml dioxane and combined with 5 mlconcentrated hydrochloric acid. The reaction mixture is refluxed for 24h with stirring. Then it is diluted with water and extracted three timeswith dichloromethane. The combined organic phases are again washed withwater, dried and the solvent is removed. The residue is purified bycolumn chromatography. The carrier used is silica gel and the eluantused is dichloromethane, to which 5% of a mixture of 90% methanol and10% saturated aqueous ammonia solution have been added.

Yield: 70 mg (0.399 mmol; 29%)

MS (ESI): 176 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

162

190

Method 33 7-amino-3,3-dimethyl-3H-isobenzofuran-1-one

250 mg (0.609 mmol) methyl 2-dibenzylamino-benzoate are combined underargon with 0.609 ml of a 1 M lithium chloride solution (THF). Thissolution is cooled to −ambient temperature and slowly 0.914 ml (1.827mmol) of a 2 M isopropyl-magnesium chloride solution are metered in.After stirring for 16 h at this temperature, 45 μl (0.609 mmol) acetoneare added dropwise and the mixture is stirred for 4 h at ambienttemperature. The reaction solution is combined with sodium hydrogencarbonate solution and extracted three times with dichloromethane. Thecombined organic phases are dried and the solvent is eliminated invacuo. The residue is purified by column chromatography. The carrierused is C18-RP-silica gel and a gradient is run through which consistsof 95% water and 5% acetonitrile at the starting point and 5% water and95% acetonitrile at the finishing point. 0.1% formic acid are added toboth the water and to the acetonitrile. The suitable fractions arefreeze-dried. This intermediate product is dissolved in 50 ml ofmethanol combined with 10 mg palladium on charcoal and hydrogenated for20 h at 5 bar hydrogen pressure and ambient temperature. Then thecatalyst is filtered off and the solvent is eliminated in vacuo. Theresidue is purified by column chromatography. The carrier used isC18-RP-silica gel and a gradient is run through which consists of 95%water and 5% acetonitrile at the starting point and consists of 5% waterand 95% acetonitrile at the finishing point. 0.1% formic acid are addedto both the water and to the acetonitrile. The suitable fractions arefreeze-dried.

Yield: 34 mg (0.192 mmol; 32%)

MS (ESI): 178 (M+H)⁺

The following compounds are prepared analogously to this process:

MS (ESI) (M + H)⁺

164

192

220

190

178

Method 347-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one

a) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate

3 g (13.625 mmol) methyl 2-cyanomethyl-6-nitro-benzoate (WO 9518097) aredissolved in 20 ml THF combined with 4.33 ml (68.788 mmol) iodomethaneand cooled to 0° C. At this temperature 40.87 ml of a 1 Mpotassium-tert-butoxide solution is slowly added dropwise. The mixtureis heated to ambient temperature and stirred for 16 h at thistemperature. The reaction mixture is diluted with ethyl acetate andextracted three times with 1 M hydrochloric acid. The combined organicphases are dried and the solvent is eliminated in vacuo.

Yield: 3.11 g (12.535 mmol; 92%)

b) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one

Reaction mixture 1

1 g (4.028 mmol) methyl 2-(cyano-dimethyl-methyl)-6-nitro-benzoate aresuspended in 20% ethanolic potassium hydroxide solution and stiffed for24 h at ambient temperature.

Reaction Mixture 2

1.9 g (47.577 mmol) sodium hydroxide are dissolved in 40 ml of watercooled to 0° C. and combined with 0.5 ml (28.899 mmol) bromine reactionmixture 1 is slowly added dropwise to this solution. After 8 h the sameamount of reaction mixture 1 is added again. The mixture is stiffed fora further 48 h at RT. Then sodium sulphite solution is added, themixture is stirred for 20 min and then acidified with potassium hydrogensulphate solution. It is extracted three times with ethyl acetate. Thecombined organic phases are dried and the solvent is eliminated invacuo. The residue is purified by column chromatography. The carrierused is silica gel and the eluant used is a mixture of cyclohexane:ethylacetate (3:1).

Yield: 67 mg (0.325 mmol, 8%)

MS (ESI): 207 (M+H)⁺

c) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one

67 mg (0.325 mmol) 3,3-dimethyl-7-nitro-2,3-dihydro-isoindol-1-one aredissolved in 50 ml of methanol and combined with 10 mg palladium oncharcoal. The mixture is hydrogenated for 16 h at 4 bar H₂ pressure andambient temperature. Then the catalyst is filtered off and the solventis eliminated in vacuo.

Yield: 50 mg (0.284 mmol, 93%)

MS (ESI): 177 (M+H)⁺

d) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one

50 mg (0.284 mmol) 3,3-dimethyl-7-amino-2,3-dihydro-isoindol-1-one aredissolved in 0.5 ml DMF and combined with 141 mg (1.021 mmol) potassiumcarbonate and 10 mg (0.028 mmol) tetrabutylammonium iodide. The mixtureis heated to 50° C. and 155 μl (1.277 mmol) benzylbromide are addeddropwise thereto. After stirring for 16 h at this temperature themixture is diluted with ethyl acetate and extracted three times with 1 Mhydrochloric acid. The combined organic phases are dried and the solventis eliminated in vacuo.

Yield: 67 mg (0.188 mmol; 66%)

MS (ESI): 357 (M+H)⁺

e)7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one67 mg (0.188 mmol)7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in1 ml (7.877 mmol) 1-bromo-2-fluoroethane and combined with 52 mg (0.376mmol) sodium hydride. After 4 h stirring at ambient temperature themixture is diluted with ethyl acetate and extracted three times with 1 Mhydrochloric acid. The combined organic phases are dried and the solventis eliminated in vacuo.

Yield: 75 mg (0.188 mmol; 100%)

MS (ESI): 403 (M+H)⁺

f) 7-amino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one

75 mg (0.188 mmol)7-dibenzylamino-2-(2-fluoro-ethyl)-3,3-dimethyl-2,3-dihydro-isoindol-1-oneare dissolved in 50 ml of methanol and combined with 10 mg palladium oncharcoal. The mixture is hydrogenated for 16 h at 5 bar H₂ pressure andambient temperature. Then the catalyst is filtered off and the solventis eliminated in vacuo.

Yield: 36 mg (0.162 mmol, 87%)

MS (ESI): 223 (M+H)⁺

Example 12-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

100 mg (0.257 mmol)2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine(method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with83 mg (0.565 mmol) 7-amino-2,3-dihydro-isoindol-1-one (method 2). 48 μlof a 4 molar solution of HCl (0.193 mmol) in 1,4-dioxane are meteredinto this reaction mixture. After two days at 50° C. the solvent iseliminated in vacuo. The crude product is purified by columnchromatography. The carrier used is silica gel and the eluant used isdichloromethane, to which 5% of a mixture of 90% methanol and 10%saturated aqueous ammonia solution have been added. The concentratedcrude product is again purified by column chromatography. The carrierused is C18-RP-silica gel and a gradient is run through which consistsof 80% water and 20% acetonitrile at the starting point and 60% waterand 40% acetonitrile at the finishing point.

Yield: 42 mg (0.084 mmol; 33%)

UV max: 318 nm

MS (ESI): 501 (M+H)⁺

¹H-NMR: 0.92 (t, 3H), 1.51-1.63 (m, 2H), 3.21-3.29 (m, 2H), 3.86 (s,3H), 4.37 (s, 2H), 7.14-7.21 (m, 1H), 7.33 (t, 1H), 7.47-7.54 (m, 1H),7.55-7.60 (m, 1H), 7.73-7.82 (m, 1H), 8.35-8.50 (m, 3H), 8.75 (s, 1H),9.09 (s, 1H), 10.66 (s, 1H)

Examples 2-17

The following compounds are prepared by an analogous method as describedin Example 1.2-(2-Methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidineand a corresponding 7-amino-2,3-dihydro-isoindol-1-one derivative(method 2) are used. N-methyl-2-pyrrolidinone or N,N-dimethylacetamideis used as solvent.

UV max MS (ESI) # A [nm] (M + H)⁺ 2

322 515 3

314 529 4

285 543 5

286/310 583 6

322 571 7

285/321 585 8

285/318 559 9

285/318 586 10

281/316 626 11

284/316 545 12

325 577 13

282/318 595 14

284/322 573 15

286, 306 607 16

325 17

318/282 607

Example 182-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(3-oxo-1,3-dihydro-isobenzofuran-4-ylamino)-5-trifluoromethyl-pyrimidine

100 mg (0.257 mmol)2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine(method 1) are dissolved in 1 ml N,N-dimethylacetamide and combined with46 mg (0.308 mmol) 7-amino-3H-isobenzofuran-1-one (Safdar Hayat et al.,Tetrahedron Lett 2001, 42(9):1647-1649). 48 μl of a 4 molar solution ofHCl (0.193 mmol) in 1,4-dioxane zudosiert metered into this reactionmixture. After 4 days at 50° C. the solvent is eliminated in vacuo. Thecrude product is purified by column chromatography. The carrier used issilica gel and the eluant used is dichloromethane, to which 4% of amixture of 90% methanol and 10% saturated aqueous ammonia solution havebeen added.

Yield: 26 mg (0.051 mmol; 20%)

UV max: 322 nm

MS (ESI): 502 (M+H)⁺

¹H-NMR: 0.92 (t, 3H), 1.51-1.63 (m, 2H), 3.22-3.28 (m, 2H), 3.86 (s,3H), 5.42 (s, 2H), 7.24-7.30 (m, 1H), 7.44-7.55 (m, 2H), 7.55-7.60 (m,H), 7.67-7.78 (m, 1H), 8.38-8.48 (m, 2H), 8.50 (s, 1H), 9.21 (s, 1H),9.64 (s, 1H)

Examples 19-37

The following compounds are prepared by analogous methods to thosedescribed in Example 1 and Example 18.2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine(method 1) is used. The corresponding aniline derivative is commerciallyobtainable, known from the literature or is prepared by the processesdescribed in method 2 and 4 to 9. N-methyl-2-pyrrolidinone orN,N-dimethylacetamide is used as solvent.

UV max MS (ESI) # A [nm] (M + H)⁺ 19

235 586 20

323/226 543 21

325 530 22

262 514 23

320 544 24

318 542 25

312 530 26

315 529 27

314 528 28

317 502 29

316 516 30

322 529 31

255 548 32

320 500 33

325 515 34

250/286/ 318 516 35

320 558 36

316 514 37

321

Example 382-(2-methoxy-4-N-propylcarbamoyl-phenylamino)-4-(4-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-5-trifluoromethyl-pyrimidine

50 mg (0.129 mmol)2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoro-methyl-pyrimidine(method 1) are dissolved in 200 μl 1,4-dioxane and combined with 25 mg(0.13 mmol) 6-amino-4-methyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one(method 10). 36 μl of a 4 molar solution of HCl (0.144 mmol) in1,4-dioxane are metered into this reaction mixture. After 4 days at 50°C. the solvent is eliminated in vacuo. The crude product is purified bycolumn chromatography. The carrier used is silica gel and the eluantused is a mixture of dichloromethane and ethyl acetate (1:1).

Yield: 23 mg (0.042 mmol; 33%)

UV max: 318 nm

MS (ESI): 545 (M+H)⁺

¹H-NMR: 0.91 (t, 3H), 1.49-1.61 (m, 2H), 3.09 (s, 3H), 3.20-3.28 (m,2H), 3.49 (t, 2H), 3.88 (s, 3H), 4.31 (t, 2H), 6.83-6.88 (m, 1H),7.34-7.45 (m, 2H), 7.50-7.54 (m, 1H), 7.88-8.00 (m, 2H), 8.37-8.44 (m,2H), 8.62 (s, 1H), 9.97 (s, 1H)

Examples 39-52

The following compounds are prepared by analogous methods to thosedescribed in Example 1 and 18.2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethylpyrimidine(method 1) is used. The corresponding aniline derivative is commerciallyobtainable, known from the literature or is prepared by the processesdescribed in method 10 and 11. N-methyl-2-pyrrolidinone orN,N-dimethylacetamide is used as solvent.

UV max MS (ESI) # A [nm] (M + H)⁺ 39

229/279/ 315 559 40

282/314 545 41

282/318 587 42

282/314 571 43

282/318 585 44

318 559 45

234/320 559 46

282/218 603 47

278/318 531 48

286/314 573 49

274/314 558 50

318 587 51

223/282/318 579 52

318 634

Example 532-[2-methoxy-4-(4-morpholin-4-yl-(1,4-trans-cyclohexyl)carbamoyl)-phenylamino]-4-(2-carbamoyl-3-fluoro-phenylamino)-5-trifluoromethyl-pyrimidine

102 mg (0.29 mmol)2-(4-carboxyamino-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine(method 12) are dissolved in 250 μl N-methyl-2-pyrrolidinone andcombined with 47 mg (0.319 mmol) 7-amino-indan-1-one (method 8). 15 μlof a 4 M solution of HCl (0.058 mmol) in 1,4-dioxane are metered intothis reaction mixture. After 16 h at 90° C. the reaction mixture isstirred into 150 ml of a aqueous 1 N hydrochloric acid. The precipitateis filtered off and dried in vacuo. 100 mg (0.174 mmol) of thisprecipitate, 150 μl (0.875 mmol) N-ethyldiisopropyl-amine, 68 mg (0.210mmol)O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and30 mg (0.163 mmol) trans-4-morpholin-4-yl-cyclohexylamine (method 13)are dissolved in 5 ml N,N-dimethylformamide. After 15 h at ambienttemperature the solvent is eliminated in vacuo. The crude product ispurified by column chromatography. The carrier used is silica gel andthe eluant used is dichloromethane, to which 7% of a mixture of 90%methanol and 10% saturated aqueous ammonia solution have been added.

Yield: 55 mg (0.100 mmol; 57%)

UV max: 318 nm

MS (ESI): 555 (M+H)⁺

¹H-NMR: 1.55-1.69 (m, 2H), 1.74-1.84 (m, 2H), 1.91-2.02 (m, 2H), 2.18(s, 3H), 2.69-2.75 (m, 2H), 2.75-2.84 (m, 2H), 3.03-3.10 (m, 2H),3.70-3.83 (m, 1H), 3.86 (s, 3H), 7.15-7.21 (m, 1H), 7.36-7.46 (m, 1H),7.48-7.54 (m, 1H), 7.54-7.58 (m, 1H), 7.71-7.79 (m, 1H), 8.18-8.25 (m,1H), 8.30-8.45 (m, 1H), 8.48 (s, 1H), 9.16 (s, 1H), 10.59 (s, 1H)

Examples 54-77

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 2, 7, 8, or 9 or known from the literature. The amine used toprepare the amide is commercially obtainable or is described in method13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 54

318 555 55

318 569 56

322 570 57

320 640 58

284, 322 556 59

282, 318 626 60

325 655 61

325 585 62

254, 286, 318 639 63

321 631 64

322 570 65

322 640 66

322 683 67

322 613 68

286, 322 654 69

286, 322 584 70

282, 322 627 71

322 670 72

286, 322 600 73

322 684 74

286, 322 614 75

322 557 76

330 732 77

325 654

Examples 78-140

The following compounds are prepared by an analogous method to thatdescribed in Example 53.2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be prepared according to method 12 or 14. The corresponding anilineis described in the supplements to method 10. The amine used to preparethe amide is commercially obtainable or is described in method 13, inthe supplements to method 13, 15 or 25.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 78

318 308 79

326 346 80

318 706 81

318 584 82

318 614 83

318 776 84

318 626 85

318 348 86

318 718 87

318 684 88

318 353 89

322 346 90

318 686 91

310 621 92

318 746 93

318 676 94

318 316 95

318 696 96

282; 310 571 97

318 614 98

318 684 99

315 559 100

314 621 101

314 676 102

318 747 103

318 656 104

318 586 105

318 (M 106

318 730 107

322 674 108

318 640 109

322 640 110

282, 318 614 111

226, 282, 318 640 112

318 614 113

626 114

318 640 115

318 640 116

318 654 117

318 668 118

318 628 119

318 600 120

318-322 614 121

318 670 122

318 654 123

318 626 124

282, 318 668 125

282, 318 642 126

282, 318 693 127

318 680 128

318 654 129

318 705 130

226, 282, 318 628 131

318 668 132

318-322 642 133

318 693 134

318-322 642 135

318 682 136

318 698 137

318-322 656 138

318-322 707 139

318-322 640 140

318-322 628

Examples 141-166

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The preparation of2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine isdescribed in method 14. The corresponding aniline is described in method10. The amine used to prepare the amide is commercially obtainable or isdescribed in method 13, 15 or 25.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 141

302 596 142

302 610 143

302 596 144

302 584 145

302 610 146

302 638 147

298 654 148

302 610 149

302 650 150

298-302 666 151

302 584 152

302 624 153

298-302 640 154

302 598 155

298-302 649 156

302 598 157

302 638 158

298-302 654 159

302 612 160

302 663 161

302 612 162

302 652 163

298-302 668 164

302 677 165

302 626 166

302 624

Example 1672-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-5-trifluoromethyl-pyrimidine

500 mg (0.958 mmol)2-[4-(4-benzyloxycarbonyl-piperazin-1-yl)-phenylamino]-4-chloro-5-trifluoromethyl-pyrimidine(method 14) are dissolved in 0.5 ml NMP, combined with 198 mg (0.960mmol) 6-amino-3,3-dimethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one(method 10) and with 25 μl (0.1 mmol) dioxanic hydrochloric acid. Thisreaction mixture is stirred for 1.5 h at 100° C. The solvent iseliminated in vacuo and the residue is purified by columnchromatography. The carrier used is C18-RP-silica gel and a gradient isrun through which consists of 95% water and 5% acetonitrile at thestarting point and consists of 5% water and 95% acetonitrile at thefinishing point. 0.1% formic acid are added to both the water and to theacetonitrile.

Yield: 0.59 g (0.86 mmol; 90%)

0.59 g (0.86 mmol) of the above-mentioned intermediate products aredissolved in 50 ml of dimethylformamide and combined with a quantity ofdistilled water such that there is no precipitation. To this solutionare added 60 mg palladium on charcoal and the mixture is hydrogenated at7 bar H₂ pressure and 20° C. for 6 h. The catalyst is filtered off andthe solvent is eliminated in vacuo. The residue is purified by columnchromatography. The carrier used is C18-RP-silica gel and a gradient isrun through which consists at the starting point of 60% water and 40%acetonitrile and at the finishing point of 15% water and 85%acetonitrile. 10 mmol/l ammonium hydrogen carbonate and 20 mmol/lammonia are dissolved in the water. The suitable fractions arefreeze-dried. The residue is dissolved in acetonitrile and combined with2 ml of a 1 M hydrochloric acid solution. Then the solvent is eliminatedin vacuo. The substance is obtained as the dihydrochloride.

Yield: 0.46 g (0.73 mmol; 85%)

UV max: 284 nm

MS (ESI): 558 (M+H)⁺

¹H-NMR: 1.19 (s, 6H), 3.19-3.28 (m, 4H), 3.41-3.49 (m, 4H), 3.80 (s,3H), 4.07 (s, 1H), 6.54-6.60 (m, 1H), 6.72-6.76 (m, 1H), 6.83-6.89 (m,1H), 7.21-7.42 (m, 2H), 7.85-8.20 (m, 1H), 8.33-8.60 (m, 1H), 8.74 (s,1H), 9.30-9.71 (m, 3H), 12.84 (s, 1H)

Example 1682-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(S)-4-oxo-2,3,10,10a-tetrahydro-1H,4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine

This compound is prepared analogously to Example 167. The aniline usedis described in method 10.

Yield: 0.23 g (0.41 mmol; 91%)

UV max: 282 nm

MS (ESI): 570 (M+H)⁺

¹H-NMR: 1.53-1.71 (m, 1H), 1.79-2.06 (m, 3H), 3.15-3.32 (m, 4H),3.32-3.55 (m, 5H), 3.58-3.72 (m, 1H), 3.72-3.94 (m, 4H), 4.00-4.23 (m,2H), 6.48-6.61 (m, 1H), 6.68-6.77 (m, 1H), 6.83-7.00 (m, 1H), 7.19-7.50(m, 2H), 7.78-8.10 (m, 1H), 8.23-8.60 (m, 1H), 9.18-9.64 (m, 3H),10.54-10.86 (m, 1H)

Example 1692-[4-(4-ethyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H,4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine

60 mg (0.11 mmol)2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(S)-4-oxo-2,3,10,10a-tetrahydro-1H,4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine(Example 168) are dissolved in 300 μl dimethylformamide and combinedwith 12 μl (0.21 mmol) acetaldehyde and 47 mg (0.21 mmol) sodiumtriacetoxyborohydride. This reaction mixture is stirred at 20° C. for 20h. The solvent is eliminated in vacuo and the residue is purified bycolumn chromatography. The carrier used is C18-RP-silica gel and agradient is run through which consists of 95% water and 5% acetonitrileat the starting point and 50% water and 50% acetonitrile at thefinishing point. 0.1% formic acid are added to both the water and to theacetonitrile. The suitable fractions are combined with 500 μl of a 1 Nhydrochloric acid and freeze-dried. The product is obtained as thedihydrochloride.

Yield: 49 mg (0.074 mmol; 71%)

UV max: 282 nm

MS (ESI): 598 (M+H)⁺

¹H-NMR: 1.23-1.37 (m, 3H), 1.57-1.72 (m, 1H), 1.80-2.06 (m, 3H),3.02-3.27 (m, 6H), 3.34-3.48 (m, 1H), 3.48-3.71 (m, 3H), 3.71-3.94 (m,7H), 6.48-6.61 (m, 1H), 6.68-6.79 (m, 1H), 6.84-6.97 (m, 1H), 7.18-7.43(m, 2H), 7.78-8.08 (m, 1H), 8.26-8.53 (m, 1H), 9.14-9.44 (m, 1H),10.49-10.74 (m, 1H), 10.80-11.08 (m, 1H)

Example 1702-[4-(4-methyl-piperazin-1-yl)-2-methoxy-phenylamino]-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H,4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino-5-trifluoromethyl-pyrimidine

To prepare this compound formaldehyde is used instead of acetaldehyde.Otherwise the method is as in Example 169.

Yield: 16 mg (0.024 mmol; 28%)

UV max: 278 nm

MS (ESI): 584 (M+H)⁺

¹H-NMR: 1.58-1.71 (m, 1H), 1.81-2.06 (m, 3H), 2.78-2.88 (m, 3H),3.00-3.23 (m, 4H), 4.03-4.21 (m, 2H), 6.48-6.59 (m, 1H), 6.69-6.78 (m,1H), 6.80-6.91 (m, 1H), 7.17-7.44 (m, 2H), 7.92-8.15 (m, 1H), 8.34 (s,1H), 8.86-9.04 (m, 1H), 10.38-10.64 (m, 2H)

Examples 171-180

The following Examples are prepared analogously to to Example 169 and170. The corresponding aniline is described in the supplements to method10.

MS (ESI) UV max (M + # A D [nm] H)⁺ 171

226, 282 572 172

250, 282 586 173

250, 282 596 174

250, 282 600 175

282 544 176

282 558 177

218; 282 586 178

282 582 179

226 558 180

226 572

Examples 181-332

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be obtained according to method 12 or 14. The corresponding anilineis described in method 11. The amine used to prepare the amide iscommercially obtainable or described in method 13, 15 and 25.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 181

318, 282, 234 380 182

238 639 183

234; 318 709 184

318, 282, 248 558 185

318, 280 613 186

316, 282, 234 342 187

318, 284, 238 307 188

318, 282, 242 342 189

314, 282, 242 600 190

318, 282, 234 328 191

318 363 192

318, 230 650 193

314 634 194

318 634 195

318 671 196

318, 230 380 197

314, 282, 250 558 198

319 705 199

318, 226 775 200

318 634 201

314 634 202

230; 318 584 203

317 572 204

318, 230 697 205

318, 234 544 206

318 669 207

318, 230 650 208

317 627 209

318, 230 599 210

318, 230 705 211

230; 322 653 212

230; 322 655 213

230; 318 669 214

230, 282, 314 634 215

318 655 216

318, 234 725 217

314, 235 586 218

318, 230 641 219

318, 226 711 220

318, 230 640 221

318 765 222

318 600 223

315 673 224

319, 226 728 225

318, 226 798 226

318, 234 655 227

230; 322 653 228

230; 318 682 229

234; 318 639 230

318, 226 695 231

234, 282, 318 598 232

230, 282, 318 653 233

234, 282, 318 723 234

318, 222 673 235

318 725 236

318, 282, 226 798 237

230; 318 641 238

230; 318 711 239

234; 318 586 240

318, 226 745 241

322 703 242

320, 226 732 243

321, 221 694 244

230, 282, 318 652 245

234, 282, 318 707 246

230, 282, 318 777 247

230, 282, 318 630 248

234, 282, 318 685 249

234, 282, 318 755 250

230, 282, 318 630 251

230, 282, 318 685 252

230, 282, 318 755 253

230; 318 695 254

230; 318 70 255

230; 318 389 256

230; 318 652 257

230 357 258

230 784 259

230 659 260

319, 230 689 261

322 703 262

322 705 263

320 719 264

226 690 265

226; 318 760 266

230 635 267

230; 318 381 268

318 812 269

318 652 270

318 707 271

318, 226 777 272

318 659 273

318 714 274

315, 239 669 275

319, 222 723 276

318, 226 793 277

316 620 278

318 675 279

318, 226 745 280

317, 226 620 281

318 675 282

318, 230 745 283

318 784 284

318 758 285

318 688 286

238, 282, 314 616 287

230, 282, 318 671 288

230, 282, 318 741 289

234, 282, 318 616 290

226, 282, 318 671 291

234, 282, 318 741 292

234, 282, 318 648 293

230, 282, 318 703 294

226, 282, 318 773 295

226, 282, 318 893 296

226, 282, 318 727 297

226, 282, 318 754 298

230, 282, 318 823 299

282, 318 669 300

282, 318 613 301

282, 318 641 302

286, 318 639 303

286, 318 627 304

286, 318 655 305

286, 318 667 306

286, 318 717 307

286, 318 689 308

286, 318 665 309

230, 286, 318 653 310

230, 282, 318 715 311

286, 322 695 312

234, 286, 318 667 313

230, 282, 318 639 314

230, 282, 318 667 315

230, 282, 318 681 316

230, 282, 318 695 317

679 318

226, 284, 318 681 319

230, 284, 318 697 320

226, 284, 314 750 321

230, 286, 318 669 322

230, 282, 318 693 323

230, 282, 314 709 324

230, 286, 314 681 325

226, 286, 314 762 326

230, 282, 318 681 327

230, 282, 314 697 328

234, 282, 318 627 329

226, 282, 318 767 330

226, 282, 318 725 331

230, 286, 318 711 332

226, 282, 318 671 333

234, 282, 314 718 334

234, 282, 318 693 335

234, 286, 318 653 336

284, 318 706 337

230, 282, 318 641 338

230, 282, 314 667 339

283, 318 655 340

230, 286, 318 699 341

230, 282, 318 750 342

230, 282, 318 627 343

250, 282, 318 667 344

230, 282, 318 683 345

238, 282, 314 641 346

230, 314 692 347

282, 318 723 348

234, 286, 314 653 349

286, 318 667 350

234, 286, 314 718 351

230, 286, 318 685

Examples 352-372

The following compounds are prepared by an analogous process to thatdescribed in Example 53 described, prepared.2-(4-carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine mayafter method 14 prepared are. The corresponding aniline is in method 11described. The amine used to prepare the amide is commerciallyobtainable or is in method 13, 15 or 25 described.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 352

222, 302 688 353

246, 298 663 354

234, 298 679 355

234, 302 623 356

298 611 357

246, 302 676 358

651 359

667 360

246, 302 611 361

298 662 362

637 363

234, 298 653 364

226, 302 597 365

302 637 366

246, 302 625 367

302 695 368

302 711 369

302 669 370

302 720 371

300 693 372

242, 302 655

Examples 373-386

The following Examples are prepared analogously to Example 169 and 170.The corresponding aniline is described in method 11.

UV max MS (ESI) # A D [nm] (M + H)⁺ 373

246 621 374

246 611 375

234 639 376

238 597 377

250 599 378

250 585 379

250 613 380

250 609 381

246 625 382

250 599 383

230 571 384

246 595 385

250 585 386

246, 286 615

Examples 387-388

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be prepared according to method 12 or 14. The corresponding anilineis described in method 4 or method 17. The amine used to prepare theamide is commercially obtainable.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 387

262, 318 569 388

278, 318 615

Examples 389-404

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be prepared according to method 12 or 14. The corresponding anilineis described in method 7, in method 18 or 19. The amine used to preparethe amide is commercially obtainable or is described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 389

284, 322 668 390

230, 285, 325 698 391

280, 325 730 392

230, 285, 325 682 393

285, 325 630 394

284, 322 686 395

285, 325 616 396

285, 322 654 397

285, 325 584 398

285, 325 598 399

285, 325 668 400

285, 325 598 401

285, 325 612 402

285, 322 700 403

285, 322 630 404

262 688

Example 4052-[4-([1,4′]bipiperidinyl-4-ylcarbamoyl)-2-methoxy-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

1150 mg (3.308 mmol)2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine(method 12 or 14) are dissolved in 2.5 ml N-methyl-2-pyrrolidinone andcombined with 883 mg (4.161 mmol)7-amino-2-(2,2-difluoro-ethyl)-2,3-dihydro-isoindol-1-one (method 2).115 μl of a 4 M solution of HCl (0.460 mmol) in 1,4-dioxane are meteredinto this reaction mixture. After 16 h at 90° C. the reaction mixture isstirred into 150 ml of an aqueous 1 N hydrochloric acid. The precipitateis filtered off and dried in vacuo.

Yield: 1626 mg (3.110 mmol; 94%)

MS (ESI): 524 (M+H)⁺

100 mg (0.191 mmol) of this precipitate, 240 μl (1.402 mmol)N-ethyldiisopropyl-amine, 89 mg (0.279 mmol)O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate and76 mg (0.267 mmol) tert-butyl 4-amino-[1,4′]bipiperidinyl-F-carboxylateare dissolved in 3 ml N,N-dimethylformamide. After 15 h at 20° C. thesolvent is eliminated in vacuo. The residue is taken up in 20 mldichloromethane and 5 ml of methanol and filtered through aluminiumoxide. The aluminium oxide is washed several times with a mixture ofdichloromethane and methanol (4:1). The solvent of the combinedfractions is eliminated in vacuo. The residue is dissolved in 5 mldichloromethane and combined with 5 ml trifluoroacetic acid. Thismixture is stirred for 3 h at 20° C. and then the solvent is eliminatedin vacuo. The crude product is purified by column chromatography. Thecarrier material used is C18-RP-silica gel and a gradient is run throughwhich consists of 90% water and 10% acetonitrile at the starting pointand 5% water and 95% acetonitrile at the finishing point. 0.1% formicacid are added both to the water and to the acetonitrile. The suitablefractions are combined with 500 μl of a 1 N hydrochloric acid andfreeze-dried. The product is obtained as the trihydrochloride.

Yield: 42 mg (0.053 mmol; 28%)

UV max: 322 nm

MS (ESI): 689 (M+H)⁺

¹H-NMR: 1.92-2.19 (m, 6H), 2.28-2.37 (m, 2H), 2.86-3.00 (m, 2H),3.07-3.19 (m, 3H), 3.84-4.18 (m, 7H), 4.59 (s, 2H), 6.15-6.47 (m, 1H),7.23-7.28 (m, 1H), 7.35-7.43 (m, 1H), 7.54-7.64 (m, 2H), 7.75-7.82 (m,1H), 8.40-8.64 (m, 3H), 8.90-9.01 (m, 1H), 9.10-9.25 (m, 2H),10.40-10.47 (m, 1H), 10.91-11.27 (m, 1H)

Examples 406-407

The following compounds are prepared by an analogous process to thatdescribed in Example 405.

UV max MS (ESI) # [nm] (M + H)⁺ 406

318 606 407

322, 286 606

Example 4082-[2-methoxy-4-(1′-methyl-[1,4′]bipiperidinyl-4-ylcarbamoyl)-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

70 mg (0.087 mmol)2-[4-([1,4′]bipiperidinyl-4-ylcarbamoyl)-2-methoxy-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine(Example 405) are dissolved in 3 ml of methanol, and combined with 8.5μl (0.508 mmol) acetic acid and with 8 μl (0.107 mmol) of a 37% aqueousformaldehyde solution. Then at 20° C. 7.0 mg (0.112 mmol) sodiumcyanoborohydride are added. This mixture is stirred for 16 h at 20° C.The solvent is eliminated in vacuo and the crude product is purified bycolumn chromatography. The carrier material used is C18-RP-silica geland a gradient is run through which consists at the starting point of95% water and 5% acetonitrile and at the finishing point of 5% water and95% acetonitrile. 0.1% formic acid are added both to the water and tothe acetonitrile. The suitable fractions are combined with 500 μl of a 1N hydrochloric acid and freeze-dried. The product is obtained as thetrihydrochloride.

Yield: 18 mg (0.022 mmol; 25%)

UV max: 322 nm

MS (ESI): 703 (M+H)⁺

Examples 409-491

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-Carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be prepared according to method 12 or 14. The corresponding anilineis described in method 2. The amine used to prepare the amide iscommercially obtainable or is described in method 13, 20 or 21.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 409

285, 320 584 410

322 716 411

326 703 412

558 413

282, 318 699 414

322, 286 668 415

322.3 724 416

322.3 362 417

322, 286 738 418

322, 286 738 419

282, 314 738 420

286, 314 738 421

286, 318 700 422

286, 322 698 423

286, 318 700 424

286, 322 712 425

286, 322 724 426

322, 286 672 427

282, 322 723 428

322, 285 602 429

326.3 616 430

322, 286 616 431

318, 286 645 432

321, 284 632 433

322, 286 618 434

318, 282 690 435

322, 282 708 436

322, 286 686 437

322, 284 722 438

322, 282 658 439

322, 285 547 440

322, 286 602 441

286.3 565 442

322, 286 620 443

322, 284 686 444

326.3 634 445

326, 286 634 446

322, 284 676 447

322.3 663 448

325.3 650 449

325.3 635 450

322, 282 620 451

322, 282 704 452

322, 282 665 453

326, 282 595 454

322, 284 677 455

322.3 664 456

326, 286 594 457

322, 282 743 458

326, 286 638 459

326, 283 681 460

318, 284 681 461

318, 286 627 462

322, 286 627 463

326, 286 648 464

322, 286 611 465

322, 286 723 466

322, 282 710 467

326, 286 654 468

326, 286 654 469

322, 284 683 470

326, 286 640 471

318, 283 710 472

326, 286 654 473

326, 286 654 474

321, 285 683 475

326, 286 630 476

322, 286 682 477

318, 286 612 478

318.3 606 479

322, 286 566 480

322, 286 621 481

318, 286 649 482

322, 286 606 483

326, 286 652 484

326, 286 648 485

322, 284 704 486

326, 286 634 487

322, 285 689 488

322, 285 703 489

322 698 490

322, 286 619 491

322, 286 689

Examples 492-621

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-carboxy-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be prepared according to method 12 or 14. The corresponding anilineis described in method 22. The amine used to prepare the amide iscommercially obtainable, described in method 13, 15, 20, 21, 23, 24 and25 or in J. Med. Chem. 2003, 46(5), 702-715.

UV max MS (ESI) # A R₃′ R₃″ [nm] (M + H)⁺ 492

H 286, 322 584 493

H 286, 322 826 494

H 284, 322 613 495

H 282, 322 640 496

H 286, 320 570 497

H 286, 322 584 498

H 282, 322 693 499

H 286, 322 686 500

H 286, 326 616 501

H 286, 326 630 502

H 282, 325 704 503

H 286, 326 634 504

H 286, 326 648 505

H 286, 322 712 506

H 322, 286 739 507

H 322, 286 645 508

H 326, 286 632 509

H 322, 286 672 510

H 322, 284 700 511

H 314, 286 616 512

H 286, 322 684 513

H 286, 322 670 514

H 282, 322 658 515

H 322, 286 632 516

H 326, 286 628 517

H 325, 286 628 518

H 326, 286 659 519

H 326 699 520

H 284, 326 616 521

H 234, 282, 314 630 522

H 326 660 523

H 326 657 524

H 645 525

H 326 627 526

H 326 660 527

H 326 659 528

H 326 692 529

H 326 644 530

H 326 628 531

H 322 662 532

H 326 699 533

H 326 602 534

H 646 535

H 326 666 536

H 326 646 537

H 326 — 538

H 322 616 539

H 318 630 540

H 318 630 541

H 274 644 542

H 326 658 543

H 286, 324 630 544

H 286, 326 658 545

H 286, 322 630 546

H 286, 326 642 547

H 286, 322 562 548

H 322-326 630 549

H 326 630 550

H 286, 322 607 551

H 646 552

H 644 553

H 326 644 554

H 322-326 658 555

H 322-326 658 556

H 286, 326 658 557

H 322-326 642 558

H 322-326 642 559

H 286, 322 656 560

H 286, 322 656 561

H 286, 322 671 562

H 286, 322 671 563

H 318 685 564

H 322-326 685 565

H 322-326 754 566

H 322-326 672 567

H 322 711 568

H 322-326 711 569

H 326 624 570

H 326 645 571

H 322-326 650 572

H 286, 326 684 573

H 286, 326 684 574

H 326 673 575

H 322 698 576

H 326, 286 646 577

H 286, 322 684 578

H 282, 322 658 579

H 322, 286 617 580

H 326, 286 644 581

H 326, 286 590 582

H 286, 326 673 583

H 326, 285 652 584

H 326, 282 722 585

H 326, 286 648 586

H 326, 285 718 587

H 326, 286 652 588

H 326, 284 652 589

H 325, 283 681 590

H 325.3 652 591

H 326.3 666 592

H 325, 283 666 593

H 325.3 648 594

H 325, 284 648 595

H 325, 284 677 596

H 325, 284 648 597

H 326, 285 662 598

H 325, 284 662 599

H 326, 282 720 600

314, 283 576 601

H 322, 286 714 602

H 286, 322 670 603

H 324, 285 614 604

H 324, 284 684 605

H 324, 285 628 606

H 324, 284 698 607

H 285, 322 630 608

H 325, 284 576 609

H 325, 284 576 610

H 326, 286 659 611

H 326, 286 646 612

H 325, 285 630 613

H 325, 284 630 614

H 325, 285 590 615

H 285, 325 642 616

H 325, 285 670 617

H 326, 286 684 618

H 326, 286 658 619

H 285, 324 684 620

H 326, 286 658 621

H 280, 320 631

Example 6222-(2-methoxy-4-[2-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethylamino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

73 mg (0.193 mmol)3-(4-amino-3-methoxy-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-propionamidehydrochloride (method 28) are dissolved in 3 ml 2-butanol and combinedwith 50 mg (0.129 mmol)2-chloro-4-(2-(2-fluorethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine(method 26). This reaction mixture is stirred for 16 h at 100° C. Thesolvent is eliminated in vacuo and the residue is purified by columnchromatography. The carrier material used is C18-RP-silica gel and agradient is run through which consists at the starting point of 90%water and 10% acetonitrile and at the finishing point of 55% water and45% acetonitrile. 0.1% formic acid are added both to the water and tothe acetonitrile. The suitable fractions are combined with 500 μl of a 1M aqueous hydrochloric acid and freeze-dried. The product is obtained asthe dihydrochloride.

Yield: 33 mg (0.045 mmol; 35%)

UV max: 314 nm

MS (ESI): 659 (M+H)⁺

¹H-NMR: 1.35-1.48 (m, 3H), 1.64-1.78 (m, 4H), 2.37-2.46 (m, 2H),3.48-3.75 (m, 4H), 3.97-4.14 (m, 1H), 4.50-4.78 (m, 3H), 5.55-5.71 (m,1H), 6.14-6.42 (m, 2H), 6.96-7.32 (m, 3H), 7.86-7.98 (m, 1H), 8.32 (s,1H), 8.84 (s, 1H), 10.41 (s, 1H)

Example 623 2-(2-fluoro-ethyl)-7 (2-{4-[4 (2hydroxy-ethyl)-1H-imidazol-2-yl]-2-methoxy-phenylamine}-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

0.07 g (0.3 mmol)2-[2-(4-amino-3-methoxy-phenyl)-1H-imidazol-4-yl]-ethanol (method 27)are suspended in 2 ml dioxane and brought into solution in theultrasound bath at 50° C. 0.8 ml (3.20 mmol) 4 N dioxanic hydrochloricacid are added. The dioxane is eliminated in vacuo, combined with 0.096g (0.247 mmol)7-(2-chloro-5-trifluoromethyl-pyrimidine-4-ylamine)-2-(2-fluoro-ethyl)-3-methyl-2,3-dihydro-isoindol-1-oneand suspended in butanol. The mixture is stirred for 16 h at 100° C. Thecrude product is purified by column chromatography. The carrier materialused is C18-RP-silica gel. A gradient is run through which consists atthe starting point of 75% water and 25% acetonitrile and at thefinishing point of 30% water and 70% acetonitrile. 0.1% ammonia is addedto the water. 23 mg of this intermediate product and 0.018 g (0.094mmol) p-toluenesulphonyl chloride are suspended in 0.9 ml oftetrahydrofuran and 0.02 ml (0.139 mmol) triethylamine and combined with0.007 g (0.057 mmol) 4-dimethylamino-pyridine. This reaction mixture isstirred for 16 h at 20° C. Then it is combined with 0.36 ml (5.064 mmol)pyrrolidine and stirred for 16 h at 60° C. The crude product is purifiedby column chromatography. The carrier material used is C18-RP-silicagel. A gradient is run through which consists of 90% water and 10%acetonitrile at the starting point and of 60% water and 40% acetonitrileat the finishing point. 0.1% formic acid is added to the water.

Yield: 7 mg (0.011 mmol, 28%)

MS (ESI): 639 (M+H)⁺

UV max: 330 nm

NMR: 1.42-1.46 (m, 3H), 1.78-2.08 (m, 6H), 2.29 (s, 1H), 3.95-4.16 (m,4H), 4.52-4.78 (m, 3H), 7.09-7.13 (m, 1H), 7.24-7.28 (m, 1H), 7.46-7.50(m, 1H), 7.52-7.58 (m, 2H), 7.64-7.67 (m, 1H), 7.82-7.88 (m, 1H),8.02-8.13 (m, 2H), 8.50-8.60 (m, 2H), 9.20-9.23 (m, 1H), 10.52-10.82 (m,2H).

Examples 624-638

The following compounds are prepared by an analogous process to thatdescribed in Example 622 or 623. The corresponding aniline is describedin method 27 and 28.

# B UV max [nm] MS (ESI) (M + H)⁺ 624

290, 326 586 625

290, 330 654 626

290, 326 625 627

326 512 628

314 685 629

290, 314 659 630

659 631

278 592 632

314 592 633

314 588 634

314 602 635

314 602 636

314 588 637

314 602 638

670

Example 6392-(4-(4-isopropyl-[1,4]diazepin-1-yl)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

50 mg (0.087 mmol)2-(4-(4-[1,4]diazepan-1-yl)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine(method from Example 622, aniline from method 28) are dissolved in 0.5ml dimethylacetamide and combined with 13 μl (0.174 mmol) acetone. 37 mg(0.175 mmol) sodium triacetoxyborohydride are added to this reactionmixture. After 16 h at 20° C. the solvent is eliminated in vacuo. Theresidue is purified by column chromatography. The carrier material usedis C18-RP-silica gel and within 15 min a gradient is run through whichconsists of 95% water and 5% acetonitrile at the starting point and 5%water and 95% acetonitrile at the finishing point. 0.1% formic acid areadded both to the water and to the acetonitrile. The suitable fractionsare combined with 500 μl of a 1 M aqueous hydrochloric acid andfreeze-dried. The product is obtained as the dihydrochloride.

Yield: 51 mg (0.074 mmol; 85%)

UV max: 314 nm

MS (ESI): 616 (M+H)⁺

¹H-NMR: 1.23-1.35 (m, 6H), 1.35-1.51 (m, 3H), 2.16-2.29 (m, 1H),2.95-3.05 (m, 1H), 3.12-3.23 (m, 1H), 3.42-3.66 (m, 6H), 3.78 (s, 3H),3.83-4.00 (m, 2H), 4.00-4.16 (m, 1H), 4.50-4.79 (m, 3H), 6.32-6.63 (m,2H), 7.08-8.59 (m, 4H), 9.24-9.76 (m, 1H), 10.67 (s, 2H)

Examples 640-648

The following compounds are prepared by an analogous process to thatdescribed in Example 639.

UV max MS (ESI) # D [nm] (M + H)⁺ 640

314 574 641

310-314 628 642

310-314 602 643

310-314 630 644

314 671 645

310-314 618 646

314 658 647

314 588

Examples 648-659

The following compounds are prepared by an analogous process to thatdescribed in Example 639. For the reductive amination2-(2-methoxy-4-piperazin-1-yl-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineis used. The aniline for preparing this compound is described in method28.

UV max MS (ESI) # D [nm] (M + H)⁺ 648

286, 314 631 649

286, 314 603 650

282, 314 643 651

282, 314 671 652

286, 314 657 653

282, 314 628 654

286, 314 657 655

286, 314 671 656

282, 314 614 657

282, 314 560 658

234, 283, 314 694 659

286, 314 574

Examples 660-666

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-Carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidinemay be prepared according to method 29. The corresponding aniline isdescribed in method 22. The amine used to prepare the amide iscommercially obtainable or described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 660

314 678/680 661

314 626/628 662

314 626/628 663

286 609/611 664

314 734/736 665

314 693/695 666

286 678/680

Examples 667-681

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-Carboxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine may beprepared according to method 14. The corresponding aniline is describedin method 22. The amine used to prepare the amide is commerciallyobtainable or described in method 13. In addition, the group R₃′ may besynthesised analogously to Example 639 by reductive amination. An amineis used which has another protected amino function in the side chain.The protective group used may be a tert-butoxycarbonyl,benzyloxycarbonyl or benzyl group. This protective group is cleaved by aprocedure familiar to the skilled man and reductive amination(analogously to Example 639) or alkylation (analogously to method 34 orWO2004052857) are the last steps in this sequence.

UV max MS (ESI) # A R₃′ R₃″ [nm] (M + H)⁺ 667

H 314 586 668

H 314 586 669

H 314 586 670

H 314 642 671

H 314 616 672

H 290 600 673

H 290 709 674

H 314 600 675

H 314 586 676

286 574 677

H 286 572 678

H 290 682 679

H 314 642 680

H 290 656 681

H 314 615

Example 6822-(2-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propionylamino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

63 mg (0.116 mmol)2-(4-acryloylamino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine(method 30) are dissolved in 1 ml of methanol and combined with 70 mg(0.699 mmol) N-methyl-piperazine. After stirring for 48 h at 20° C. thesolvent is eliminated in vacuo. The residue is purified by columnchromatography. The carrier material used is C18-RP-silica gel and agradient is run through within 20 min which consists of 95% water and 5%acetonitrile at the starting point and of 2% water and 98% acetonitrileat the finishing point. 0.1% formic acid are added both to the water andto the acetonitrile. The suitable fractions are combined with 500 μl ofa 1 M aqueous hydrochloric acid and freeze-dried. The product isobtained as the dihydrochloride.

Yield: 58 mg (0.081 mmol; 70%)

UV max: 282 nm

MS (ESI): 645 (M+H)⁺

¹H-NMR: 1.42 (d, 3H), 2.18 (s, 3H), 2.29-2.43 (m, 4H), 2.65-2.70 (m,2H), 3.50-3.62 (m, 1H), 3.72 (s, 3H), 4.00-4.12 (m, 1H), 4.52-4.76 (m,3H), 7.12-7.17 (m, 1H), 7.12-7.42 (m 4H), 7.51 (s, 1H), 8.17 (s, 1H),8.38 (s, 1H), 9.08 (s, 1H), 10.18 (s, 1H), 10.46 (s, 1H)

Examples 683-692

The following compounds are prepared by an analogous process to thatdescribed in Example 682.

UV max MS (ESI) # E [nm] (M + H)⁺ 683

282 661 684

282 673 685

282 701 686

282 645 687

282 685 688

282 616 689

282 713 690

282 630 691

282 632 692

282 602

Examples 693-704

The following compounds are prepared by an analogous process to thatdescribed in Example 682.2-(4-(2-Bromo-acetylamino)-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineor2-(4-(2-bromo-acetylamino)-2-bromo-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineor2-[5-(2-bromo-acetylamino)-pyridin-2-ylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine,which are described in method 30, are used as educt for the nucleophilicsubstitution.

UV max MS (ESI) # B [nm]: (M + H)⁺: 693

282 685 694

282 685 695

314 659 696

282 645 697

282 644 698

282 618 699

282 602 700

282 687 701

322 573 702

322 630 703

222 650 704

278 707

Example 7052-(2-methoxy-4-[3-(3-pyrrolidin-1-yl-ethyl)-ureido]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

70 mg (0.135 mmol)2-(4-carboxy-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine(analogously to Example 53) are dissolved in 2 ml of toluene andcombined with 190 μl (1.348 mmol) triethylamine and 60 μl (0.270 mmol)diphenylphosphorylazide.

This reaction mixture is stirred for 48 h at 20° C. Then the temperatureof the suspension is adjusted to 95° C. for 2 h, whereupon a clear brownsolution is formed. Then 31 mg (0.270 mmol) 1-(2-aminoethyl)-pyrrolidineare added and the mixture is again stirred for 1 h at 95° C. The solventis eliminated in vacuo. The residue is purified by columnchromatography. The carrier used is C18-RP-silica gel and within 15 mina gradient is run through which consists of 95% water and 5%acetonitrile at the starting point and consists of 2% water and 98%acetonitrile at the finishing point. 0.1% formic acid are added to boththe water and to the acetonitrile. The suitable fractions are made basicwith 5 M sodium hydroxide solution and extracted 4 times with 50 mldichloromethane. The combined organic phases are dried and the solventis eliminated in vacuo.

Yield: 42 mg (0.067 mmol; 50%)

UV max: 282 nm

MS (ESI): 631 (M+H)⁺

¹H-NMR: 1.42-1.48 (m, 3H), 1.69-1.79 (m, 4H), 3.22-3.28 (m, 2H),3.49-3.62 (m, 1H), 3.70 (s, 3H), 3.99-4.12 (m, 1H), 4.53-4.76 (m, 3H),6.17 (s, 1H), 6.84-6.91 (m, 1H), 7.15-7.33 (m, 3H), 7.40 (s, 1H), 8.36(s, 1H), 8.76 (s, 1H), 9.01 (s, 1H), 10.44 (s, 1H)

Example 7062-(2-methoxy-4-ureido-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

This compound is prepared analogously to Example 705.

UV max: 282/314 nm

MS (ESI): 534 (M+H)⁺

¹H-NMR: 1.42 (d, 3H), 3.48-3.64 (m, 1H), 3.69 (s, 3H), 3.98-4.13 (m,1H), 4.50-4.77 (m, 3H), 5.89 (s, 2H), 6.94 (d, 1H), 7.16-7.30 (m, 2H),7.36 (s, 1H), 8.33-8.41 (m, 2H), 8.38 (s, 1H), 8.73 (s, 1H), 9.00 (s,1H), 10.44 (s, 1H)

Example 7072-(2-methoxy-4-[(1-methyl-piperidin-4-carbonyl)-amino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

Starting from2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine(method 30) the above-mentioned product is prepared using an amidelinking method familiar to the skilled man (cf. also Example 53 or1032). The substance is obtained as a free base.

UV max: 282 nm

MS (ESI): 616 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): 1.51 (d, 3H), 2.25-2.32 (m, 1H), 2.36 (s, 3H),3.00-3.07 (m, 2H), 3.53-3.65 (m, 1H), 3.92 (s, 3H), 4.13-4.27 (m, 1H),4.56-4.77 (m, 3H), 6.84 (d, 1H), 7.07 (d, 1H), 7.44 (s, 1H), 7.47-7.54(m, 1H), 7.57 (s, 1H), 7.62 (s, 1H), 8.16-8.24 (m, 1H), 8.39 (s, 1H),8.60-8.68 (m, 1H), 10.42 (s, 1H)

Examples 708-795

Using an analogous method to that described in Example 53 a primaryamine which has another protected amino function in the side chain iscoupled to2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine.The protective group used may be a tert-butoxycarbonyl,benzyloxycarbonyl or benzyl group. This protective group is cleavedusing a procedure familiar to the skilled man and reductive amination(analogously to Example 639) or alkylation (analogously to method 34 orWO2004052857) are the final steps in this sequence.

MS UV (ESI) max (M + # R₃′ [nm] H)⁺ 708

285, 322 706 709

285, 322 656 710

285, 322 630 711

322, 286 644 712

325, 286 699 713

282, 318 644 714

326 685 715

326 658 716

326 699 717

326 630 718

326 644 719

322 644 720

326 656 721

326 678 722

314 630 723

322 641 724

326 712 725

326 642 726

322 642 727

318 672 728

301 686 729

326 588 730

326 642 731

326 670 732

326 642 733

326 630 734

326 699 735

310 616 736

326 656 737

322 630 738

326 656 739

326 656 740

266 652 741

326 629 742

326 671 743

326 630 744

326 642 745

326 602 746

326 628 747

326 616 748

326 602 749

322 652 750

326 646 751

326 672 752

326 616 753

326 616 754

326 685 755

322 616 756

318 713 757

286, 322 588 758

226, 286, 322 602 759

322- 326 656 760

322- 326 699 761

322- 326 670 762

322- 326 699 763

322 713 764

326 685 765

322 684 766

326 642 767

322- 326 656 768

322- 326 685 769

322- 326 630 770

286, 322 670 771

286, 322 670 772

322- 326 644 773

322 684 774

322- 326 658 775

322 686 776

322- 326 727 777

322- 326 674 778

322- 326 684 796

322- 326 698 780

286, 322 630 781

282, 314 616 782

322, 286 686 783

326 684 784

324, 286 656 785

326, 286 685 786

322, 286 715 787

322, 286 673 788

285, 322 616 789

285, 322 630 790

285, 322 686 791

285, 322 686 792

326 644 793

322 630 794

326 631 795

326 660

Example 7962-[2-methoxy-4-(2-methyl-2-pyrrolidin-1-yl-propylcarbamoyl)-phenylamino]-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

200 mg (0.385 mmol)2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidine(analogously to Example 53) are dissolved in 1 ml of dimethylformamidecooled to 0° C. and combined with 520 μl (3.038 mmol)diisopropylethylamine and 160 mg (0.498 mmol)O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate.This solution is slowly added dropwise after 10 min to 56 μl (0.539mmol) 1,2-diamino-2-methylpropane, which is dissolved in 300 μldimethylformamide. The reaction mixture is stirred for 24 h at 20° C.and then the solvent is eliminated in vacuo. The residue is purified bycolumn chromatography. The carrier used is C18-RP-silica gel and within15 min a gradient is run through which consists at the starting point of90% water and 10% acetonitrile and at the finishing point of 50% waterand 50% acetonitrile. 0.1% formic acid are added to both the water andto the acetonitrile. The suitable fractions are freeze-dried. Thisintermediate product is combined with 70 mg (0.515 mmol) potassiumcarbonate and with 84 mg (0.506 mmol) potassium iodide and suspended in2 ml acetonitrile. 20 μl (0.170 mmol)1,4-dibromobutane are added to thismixture and it is stirred under reflux conditions for 16 h. Then thesolvents are solvent eliminated in vacuo and the residue is purified bycolumn chromatography. The carrier used is C18-RP-silica gel and within15 min a gradient is run through which consists at the starting point of90% water and 10% acetonitrile and at the finishing point of 50% waterand 50% acetonitrile. 0.1% formic acid are added to both the water andto the acetonitrile. The suitable fractions are combined with 0.5 ml 1 Nhydrochloric acid and freeze-dried. The product is obtained as thedihydrochloride.

Yield: 20 mg (0.032 mmol, 8%)

UV max: 325 nm

MS (ESI): 644 (M+H)⁺

¹H-NMR (400 MHz): 1.30-1.47 (m, 9H), 1.85-2.01 (m, 4H), 3.20-3.31 (m,2H), 3.91 (s, 3H), 3.99-4.15 (m, 1H), 4.51-4.78 (m, 3H), 7.23-7.29 (m,1H), 7.39-7.47 (m, 1H), 7.63-7.69 (m, 1H), 7.73-7.77 (m, 1H), 7.79-7.87(m, 1H), 8.40-8.59 (m, 2H), 8.75-8.82 (m, 1H), 9.16-9.21 (m, 1H),10.50-10.63 (m, 2H)

Examples 797-806

The following compounds are prepared by an analogous method to thatdescribed in Example 796:

UV max MS (ESI) # R₃′ [nm] (M + H)⁺ 797

285, 325 642 798

284, 325 642 799

325, 285 644 800

325, 285 644 801

325, 285 644 802

325, 285 656 803

325, 285 658 804

325, 284 658 805

326, 286 670 806

324, 285 670

Examples 807-821

The following compounds are prepared by an analogous process to thatdescribed in Example 53. The corresponding aniline is described inmethod 31. The amine used to prepare the amide is commerciallyobtainable or is described in method 13, 21 or in method 25.

UV max MS (ESI) # R₃′ [nm] (M + H)⁺ 807

286, 322 686 808

286, 322 616 809

286, 322 630 810

286, 322 616 811

286, 322 712 812

322, 286 684 813

689 814

278 689 815

322 630 816

286, 326 645 817

285, 322 659 818

285, 322 616 819

285, 322 630 820

630 821

322, 286 630

Examples 822-885

The following compounds are prepared by an analogous process to thatdescribed in Example 53. The corresponding aniline is described inmethod 31. The amine used to prepare the amide is commerciallyobtainable, described in method 13, 15, 20, 21, 23, 24 and 25 or in J.Med. Chem. 2003, 46(5), 702-715.

UV max MS (ESI) # R₃′ [nm] (M + H)⁺ 822

286, 322 686 823

325, 284 616 824

286, 326 630 825

286, 322 616 826

286, 318 712 827

286, 322 684 828

326 645 829

316 689 830

322 689 831

616 832

318 630 833

326 588 834

322 630 835

286, 322 630 836

658 837

322-326 602 838

322-326 616 839

322 616 840

322-326 616 841

322-326 630 842

322-326 630 843

286, 322 644 844

286, 322 642 845

286, 322 642 846

286, 322 656 847

282, 318 630 848

282, 322 630 849

286, 318 671 850

286, 322 630 851

286, 322 630 852

286, 322 644 853

322-326 672 854

322 672 855

286, 322 725 856

286, 322 725 857

322-326 685 858

286, 322 713 859

286, 322 713 860

286, 322 644 861

286, 322 644 862

318-322 645 863

286, 322 658 864

286, 322 699 865

286, 322 699 866

326 709 867

322 697 868

322 697 869

318 695 870

290.3 693 871

322 695 872

286, 322 753 873

286, 326 642 874

286, 322 645 875

322, 286 659 876

282, 322 684 877

324, 284 646 878

286, 322 670 879

325, 284 630 880

322, 286 630 881

322, 286 684 882

325, 286 670 883

322, 286 646 884

326, 286 644 885

325, 285 630

Examples 886-891

The following compounds are prepared by an analogous process to thatdescribed in Example 622 or 623. The corresponding aniline is describedin method 27 or 28.

UV max MS (ESI) # B [nm] (M + H)⁺ 886

314 685 887

314 685 888

286, 310 685 889

282, 314 699 890

338 656 891

314 588

Examples 892-894

The following compounds are prepared by an analogous process to thatdescribed in Example 53.2-(4-carboxy-2-bromo-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidineis described in method 29. The corresponding aniline is described inmethod 31. The amine used to prepare the amide is commerciallyobtainable.

UV max MS (ESI) # R₃′ [nm] (M + H)⁺ 892

314 665 893

270 665 894

270 680

Example 8952-(2-methoxy-4-[(1-methyl-piperidin-4-carbonyl)-amino]-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineEnantiomer 1

Starting from2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineenantiomer 1 (analogously to method 30) the above-mentioned product isprepared by an amide linking method familiar to the skilled man (cf.also Example 1032). It is obtained as the dihydrochloride.

UV max: 310 nm

MS (ESI): 616 (M+H)⁺

¹H-NMR (500 MHz): 1.42 (d, 3H), 1.69-1.77 (m, 2H), 1.77-1.84 (m, 2H),1.94-2.03 (m, 2H), 2.23 (s, 3H), 2.29-2.38 (m, 1H), 2.86-2.93 (m, 2H),3.72 (s, 3H), 4.00-4.12 (m, 1H), 4.52-4.75 (m, 3H), 7.16 (d, 3H),7.18-7.24 (m, 1H), 7.32-7.41 (m, 1H), 7.57 (s, 1H), 8.18 (s, 1H), 8.38(s, 1H), 9.07 (s, 1H), 9.95 (s, 1H), 10.46 (s, 1H)

Example 8962-(2-methoxy-4-(2-pyrrolidin-1-yl-acetylamino)-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineEnantiomer 1

Starting from2-(4-amino-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidineEnantiomer 1 (analogously to method 30) the above-mentioned product isprepared by an amide linking method familiar to the skilled man (cf.also Example 1032). It is obtained as the dihydrochloride.

UV max: 282 nm

MS (ESI): 602 (M+H)⁺

¹H-NMR (500 MHz): 1.43 (d, 3H), 1.87-2.00 (m, 2H), 2.00-2.10 (m, 2H),3.12-3.22 (m, 2H), 3.74 (s, 3H), 4.00-4.13 (m, 1H), 4.28-4.32 (m, 2H),4.53-4.76 (m, 3H), 7.19-7.49 (m, 4H), 7.51 (s, 1H), 8.41 (s, 1H), 9.26(s, 1H), 10.20-10.31 (m, 1H), 10.54 (s, 1H), 10.86 (s, 1H)

Examples 897-952

Using a method analogous to that described in Example 53 a primary aminewhich has another protected amino function in the side chain is coupledto2-(4-carboxy-2-methoxy-phenylamino)-4-[2-(2-fluoro-ethyl)-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino]-5-trifluoromethyl-pyrimidineEnantiomer 1. The protective group used may be a tert-butoxycarbonyl,benzyloxycarbonyl or benzyl group. This protective group is cleavedusing a procedure familiar to the skilled man and reductive amination(analogously to Example 639) or alkylation (analogously to method 34 orWO2004052857) are the final steps in this sequence.

UV max MS (ESI) # R₃′ [nm] (M + H)⁺ 897

672 898

322 644 899

326 630 900

326 630 901

322 644 902

322 642 903

322 658 904

326 615 905

322 656 906

326 658 907

326 644 908

322 644 909

322 670 910

306 686 911

326 630 912

666 913

286, 322 656 914

286, 322 656 915

286, 318 670 916

286, 322 713 917

286, 322 670 918

286.3 713 919

286, 322 642 920

286, 322 672 921

286, 322 672 922

286, 322 644 923

286, 322 670 924

286, 322 700 925

286, 322 700 926

286, 322 670 927

326 713 928

322-326 700 929

322-326 644 930

322 658 931

322-326 713 932

322 700 933

322-326 644 934

322 658 935

322-326 714 936

322 714 937

322 662 938

322-326 662 939

676 940

322-326 680 941

286, 322 648 942

230, 286, 318 662 943

384, 324 668 944

282, 322 670 945

282, 322 696 946

228, 284, 322 642 947

226, 286, 322 672 948

286, 322 644 949

324, 284 644 950

285, 322 616 951

285, 325 630 952

285, 325 616

Examples 953-958

The following compounds are prepared by a method analogous to thatdescribed in Example 796:

UV max MS (ESI) # R₃′ [nm] (M + H)⁺ 953

326, 286 658 954

325, 285 670 955

325, 285 670 956

325, 284 644 957

325, 284 658 958

325, 285 672

Example 9592-(2-methoxy-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenylamino)-4-(2-(2-fluoro-ethyl)-1-ethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

The racemic synthesis of the above-mentioned compound is carried outusing by a method analogous to that described in Example 53. Thecorresponding aniline is described in method 22. The two enantiomers areisolated by preparative chromatography:

column: 250×4.6 mm CHIRALPAKADH®

eluant: 25 ethanol/75 methanol (v/v) (0.03% triethylamine is added toeach solvent)

flow rate: 0.5 ml/min

temperature: 20° C.

The enantiomer that elutes first is referred to as Enantiomer 1 andbears the symbol *1 in the chemical formula.

Enantiomer 1

retention time: 9.96 min

The enantiomer that elutes second is referred to as Enantiomer 2 andbears the symbol *2 in the chemical formula.

Enantiomer 2

retention time: 12.60 min

Examples 960-976

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 22. The amine used to prepare the amide is commerciallyobtainable or is described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 960

280, 320 654 961

282, 318 962

286, 322 680 963

286, 326 630 964

286, 326 644 965

286, 326 630 966

286, 326 659 967

286, 326 630 968

286, 322 644 969

286, 326 644 970

286, 326 644 971

286, 326 714 972

286, 322 632 973

286, 326 646 974

286, 326 660 975

282, 326 685 976

282, 326 659

Examples 977-980

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 6. The amine used to prepare the amide is described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 977

234, 282, 318 655 978

226, 282, 318 655 979

222, 282, 318 641 980

230, 282, 314 671

Examples 981-999

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 32. The amine used to prepare the amide is commerciallyobtainable or described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 981

318 612 982

318 583 983

322 599 984

639 985

286 706 986

322 597 987

318 679 988

286 653 989

322 611 990

322 583 991

318 625 992

318 597 993

318 598 994

318 569 995

322 585 996

286 639 997

318 626 998

318 599 999

318 318

Examples 1000-1024

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 33. The amine used to prepare the amide is commerciallyobtainable or described in method 13 or 21.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 1000

282, 322 614 1001

282, 322 841 1002

282, 326 571 1003

280, 322 655 1004

280, 325 655 1005

280, 322 669 1006

280, 325 599 1007

282, 327 613 1008

280, 322 697 1009

282, 325 627 1010

283, 328 641 1011

280, 325 585 1012

280, 325 599 1013

326, 283 585 1014

282, 327 599 1015

322-326 597 1016

326 611 1017

280, 325 585 1018

280, 325 614 1019

280, 325 585 1020

280, 322 599 1021

280, 325 641 1022

280, 325 599 1023

280, 325 585 1024

280, 322 663

Examples 1025-1032

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 10. The amine used to prepare the amide is commerciallyobtainable or described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 1025

318 648 1026

318 359 1027

322 662 1028

322 662 1029

322 664 1030

226, 318 678 1031

226, 318 691 1032

322 648

Examples 1033-1035

The following compounds are prepared by an analogous method to thatdescribed in Example 53. The corresponding aniline is described inmethod 2. The amine used to prepare the amide is described in method 13.

MS (ESI) # R₃′ (M + H)⁺ salt form 1033

701 base 1034

645 formate 1035

631 formate

Example 1036(2-methoxy-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenylamino)-4-(2-(2-fluoro-ethyl)-1,1-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-trifluoromethyl-pyrimidine

The above-mentioned compound is prepared by a method analogous to thatdescribed in Example 53. The corresponding aniline is described inmethod 34. The amine used to prepare the amide is commerciallyobtainable. The substance is obtained as the dihydrochloride.

UV max: 326, 286 nm

MS (ESI): 630 (M+H)⁺

¹H-NMR (400 MHz): 1.44-1.50 (m, 6H), 1.84-1.95 (m, 2H), 1.98-2.07 (m,2H), 3.02-3.12 (m, 2H), 3.62-3.70 (m, 4H), 3.71-3.76 (m, 1H), 3.77-3.81(m, 1H), 3.89 (s, 3H), 4.57-4.61 (m, 1H), 4.69-4.73 (m, 1H), 7.27-7.31(m, 1H), 7.39-7.45 (m, 1H), 7.55-7.59 (m, 1H), 7.63-7.66 (m, 1H),7.84-7.88 (m, 1H), 8.44-8.55 (m, 2H), 8.77-8.82 (m, 1H), 9.11-9.15 (m,1H), 9.91-10.03 (m, 1H), 10.51-10.55 (m, 1H)

Example 10372-(2-methoxy-4-[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-phenylamino)-4-(2-(2-fluoro-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-acetyl-pyrimidine

50 mg (0.104 mmol)2-(4-carboxy-2-methoxy-phenylamino)-4-(2-(2-fluoro-ethyl)-3-oxo-2,3-dihydro-1H-isoindol-4-ylamino)-5-acetyl-pyrimidine(prepared by an analogous process to that described in Example 622 or623) are dissolved in 0.5 ml of dimethylformamide and combined with 72μl (0.520 mmol) and 34 mg (0.104 mmol)O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate.After stirring for 20 min at 20° C., 23 mg (0.156 mmol)2-(4-methylpiperazin-1-yl)-ethylamine are added. The reaction iscompleted after 2 h at 20° C. Then the solvent is eliminated in vacuoand the residue is purified by column chromatography. The carrier usedis C18-RP-silica gel and a gradient is run through within 20 min whichconsists of 95% water and 5% acetonitrile at the starting point andconsists of 5% water and 95% acetonitrile at the finishing point. 0.1%formic acid are added to both the water and to the acetonitrile. Thesuitable fractions are combined with 500 μl of a 1 M aqueoushydrochloric acid and freeze-dried. The product is obtained as thetrihydrochloride.

UV max: 326 nm

MS (ESI): 605 (M+H)⁺

¹H-NMR (500 MHz): 2.53-2.58 (m, 3H), 2.80-2.92 (m, 3H), 3.62-3.88 (m,9H), 3.88-4.01 (m, 4H), 4.54 (s, 2H), 4.58-4.66 (m, 1H), 4.69-4.77 (m,1H), 7.14-7.32 (m, 1H), 7.32-7.50 (m, 1H), 7.50-7.59 (m, 1H), 7.63-7.75(m, 1H), 7.78-8.01 (m, 1H), 8.29-8.60 (m, 1H), 8.73-8.99 (m, 2H),9.03-9.18 (m, 1H), 12.31-12.41 (m, 1H)

Examples 1038-1060

The following compounds are prepared by an analogous method to thatdescribed in Example 1037. The aniline used is described in method 28.

The amine used to prepare the amide is commercially obtainable ordescribed in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 1038

326 660 1039

326 646 1040

328 576 1041

318 672 1042

326 605 1043

330 590 1044

318 663 1045

330 604 1046

326 686 1047

326 604 1048

330 590 1049

326 713 1050

330 590 1051

250 614 1052

334-338 600 1053

334-338 614 1054

338 600 1055

338 670 1056

334 696 1057

330 622 1058

327 340 1059

330 608 1060

330 632

Examples 1061-1069

The following compounds are prepared by an analogous method to thatdescribed in Example 622 or 623. The corresponding aniline is describedin method 28.

UV max MS (ESI) # A B [nm] (M + H)⁺ 1061

254, 316 552 1062

254, 314 548 1063

250 598 1064

254, 318 588 1065

250 518 1066

252, 318 606 1067

250, 310 566 1068

254, 318 552 1069

262; 314- 318 566

Examples 1070-1071

The following compounds are prepared by an analogous method to thatdescribed in Example 622 or 623 and 53. The corresponding aniline isdescribed in method 28. The amine used to prepare the amide iscommercially obtainable or described in method 13.

UV max MS (ESI) # A R₃′ [nm] (M + H)⁺ 1070

330 608 1071

330 678

Examples 1072-1085

The following compounds are prepared by an analogous method to thatdescribed in Example 1037. The corresponding aniline is described inmethod 28. The amine used to prepare the amide is commerciallyobtainable or described in method 13.

UV max MS (ESI) # Z R₃′ [nm] (M + H)⁺ 1072

285, 320 674 1073

326 663 1074

306 596 1075

326 593 1076

262 596 1077

326 593 1078

318 652 1079

325 582 1080

319 582 1081

302 666 1082

322 626 1083

318 626 1084

286, 318 612 1085

280, 325 572

Biological Properties

As demonstrated by DNA staining followed by FACS analysis, theinhibition of proliferation brought about by the compounds according tothe invention is mediated above all by the arrest of the cells in theG2/M phase of the cell cycle. The cells arrest, depending on the type ofcell used, for a specific length of time in this cell cycle phase beforeprogrammed cell death is initiated. An arrest in the G2/M phase of thecell cycle may be initiated e.g. by the inhibition of specific cellcycle kinases. On the basis of their biological properties the compoundsof general formula I according to the invention, their isomers and thephysiologically acceptable salts thereof are suitable for treatingdiseases characterised by excessive or anomalous cell proliferation.

Such diseases include for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours; skin diseases (e.g. psoriasis); bone diseases;cardiovascular diseases (e.g. restenosis and hypertrophy). They are alsouseful for protecting proliferating cells (e.g. hair, intestinal, bloodand progenitor cells) from DNA damage caused by radiation, UV treatmentand/or cytostatic treatment (Davis et al., 2001). The new compounds maybe used for the prevention, short- or long-term treatment of theabove-mentioned diseases, also in combination with other activesubstances used for the same indications, e.g. cytostatics, steroids orantibodies.

The activity of the compounds according to the invention on variouskinases, for example on serine-threonine kinase PLK-1, was determined byin vitro kinase assays with recombinantly produced protein. In thisassay the compounds exhibit a good to very good effect on PLK1, i.e. forexample an IC50 value of less than 1 μmol/L, usually less than 0.1μmol/L.

Example PLK-1 Kinase Assay

Recombinant human PLK1 enzyme linked to GST at its N-terminal end isisolated from insect cells infected with baculovirus (Sf21).Purification is carried out by affinity chromatography on glutathionesepharose columns.

4×10⁷ Sf21 cells (Spodoptera frugiperda) in 200 ml of Sf-900 II Serumfree insect cell medium (Life Technologies) are seeded in a spinnerflask. After 72 hours' incubation at 27° C. and 70 rpm, 1×10⁸ Sf21 cellsare seeded in a total of 180 ml medium in a new spinner flask. Afteranother 24 hours, 20 ml of recombinant Baculovirus stock suspension areadded and the cells are cultivated for 72 hours at 27° C. at 70 rpm. 3hours before harvesting, okadaic acid is added (Calbiochem, finalconcentration 0.1 μM) and the suspension is incubated further. The cellnumber is determined, the cells are removed by centrifuging (5 minutes,4° C., 800 rpm) and washed 1× with PBS (8 g NaCl/l, 0.2 g KCl/l, 1.44 gNa₂HPO₄/l, 0.24 g KH₂PO4/l). After centrifuging again the pellet isflash-frozen in liquid nitrogen. Then the pellet is quickly thawed andresuspended in ice-cold lysing buffer (50 mM HEPES pH 7.5, 10 mM MgCl₂,1 mM DTT, 5 μg/ml leupeptin, 5 μg/ml aprotinin, 100 μM NaF, 100 μM PMSF,10 mM β-glycerolphosphate, 0.1 mM Na₃VO₄, 30 mM 4-nitrophenylphosphate)to give 1×10⁸ cells/17.5 ml. The cells are lysed for 30 minutes on ice.After removal of the cell debris by centrifugation (4000 rpm, 5 minutes)the clear supernatant is combined with glutathione sepharose beads (1 mlresuspended and washed beads per 50 ml of supernatant) and the mixtureis incubated for 30 minutes at 4° C. on a rotating board. Then the beadsare washed with lysing buffer and the recombinant protein is eluted fromthe beads with 1 ml eluting buffer/ml resuspended beads (eluting buffer:100 mM Tris/HCl pH=8.0, 120 mM NaCl, 20 mM reduced glutathione (SigmaG-4251), 10 mM MgCl₂, 1 mM DTT). The protein concentration is determinedby Bradford Assay.

Assay

The following components are combined in a well of a 96-wellround-bottomed dish (Greiner bio-one, PS Microtitre plate No. 650101):

-   -   10 μl of the compound to be tested in variable concentrations        (e.g. beginning at 300 μM, and dilution to 1:3) in 6% DMSO, 0.5        mg/ml casein (Sigma C-5890), 60 mM β-glycerophosphate, 25 mM        MOPS pH=7.0, 5 mM EGTA, 15 mM MgCl₂, 1 mM DTT    -   20 μl substrate solution (25 mM MOPS pH=7.0, 15 mM MgCl₂, 1 mM        DTT, 2.5 mM EGTA, 30 mM β-glycerophosphate, 0.25 mg/ml casein)    -   20 μl enzyme dilution (1:100 dilution of the enzyme stock in 25        mM MOPS pH=7.0, 15 mM MgCl₂, 1 mM DTT)    -   10 μl ATP solution (45 μM ATP with 1.11×10⁶ Bq/ml        gamma-P33-ATP).

The reaction is started by adding the ATP solution and continued for 45minutes at 30° C. with gentle shaking (650 rpm on an IKA SchüttlerMTS2). The reaction is stopped by the addition of 125 μl of ice-cold 5%TCA per well and incubated on ice for at least 30 minutes. Theprecipitate is transferred by harvesting onto filter plates (96-wellmicrotitre filter plate: UniFilter-96, GF/B; Packard; No. 6005177), thenwashed four times with 1% TCA and dried at 60° C. After the addition of35 μl scintillation solution (Ready-Safe; Beckmann) per well the plateis sealed shut with sealing tape and the amount of P33 precipitated ismeasured with the Wallac Betacounter. The measured data are evaluatedusing the standard Graphpad software (Levenburg-Marquard Algorhythmus).

The anti-proliferative activity of the compounds according to theinvention is determined in the cytotoxicity test on cultivated humantumour cells and/or in a FACS analysis, for example on HeLa S3 cells. Inboth test methods the compounds exhibit good to very good activity, i.e.for example an EC50 value in the HeLa S3 cytotoxicity test of less than5 mmol/L, generally less than 1 μmol/L.

Measurement of Cytotoxicity on Cultivated Human Tumour Cells

To measure cytotoxicity on cultivated human tumour cells, cells ofcervical carcinoma tumour cell line HeLa S3 (obtained from American TypeCulture Collection (ATCC)) are cultivated in Ham's F12 Medium (LifeTechnologies) and 10% foetal calf serum (Life Technologies) andharvested in the log growth phase. Then the HeLa S3 cells are placed in96-well plates (Costar) at a density of 1000 cells per well andincubated overnight in an incubator (at 37° C. and 5% CO2), while oneach plate 6 wells are filled with medium alone (3 wells as the mediumcontrol, 3 wells for incubation with reduced AlamarBlue reagent). Theactive substances are added to the cells in various concentrations(dissolved in DMSO; DMSO final concentration: 0.1%) (in each case as atriple measurement). After 72 hours incubation 20 μl AlamarBlue reagent(AccuMed International) are added to each well, and the cells areincubated for a further 5-7 hours. As a control, 20 μl reducedAlamarBlue reagent is added to each of 3 wells (AlamarBlue reagent,which is autoclaved for 30 min) After incubation the colour change ofthe AlamarBlue reagent in the individual wells is determined in a PerkinElmer fluorescence spectrophotometer (excitation 530 nm, emission 590nm, slits 15, integrate time 0.1). The amount of AlamarBlue reagentreacted represents the metabolic activity of the cells. The relativecell activity is calculated as a percentage of the control (HeLa S3cells without inhibitor) and the active substance concentration whichinhibits the cell activity by 50% (IC50) is derived. The values arecalculated from the average of three individual measurements—withcorrection of the dummy value (medium control).

FACS Analysis

Propidium iodide (PI) binds stoichiometrically to double-stranded DNA,and is thus suitable for determining the proportion of cells in the G1,S, and G2/M phase of the cell cycle on the basis of the cellular DNAcontent. Cells in the G0 and G1 phase have a diploid DNA content (2N),whereas cells in the G2 or mitosis phase have a 4N DNA content.

For PI staining, for example, 1×10⁶ HeLa S3 cells are seeded onto a 75cm2 cell culture flask, and after 24 h either 0.1% DMSO is added ascontrol or the substance is added in various concentrations (in 0.1%DMSO). The cells are incubated for 24 h with the substance or with DMSObefore the cells are washed 2× with PBS and then detached withtrypsin/EDTA. The cells are centrifuged (1000 rpm, 5 min, 4° C.), andthe cell pellet is washed 2× with PBS before the cells are resuspendedin 0.1 ml PBS. Then the cells are fixed with 80% ethanol for 16 hours at4° C. or alternatively for 2 hours at −20° C. The fixed cells arecentrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and thencentrifuged again. The cell pellet is resuspended in 2 ml 0.25% TritonX-100 in PBS, and incubated on ice for 5 min before 5 ml PBS are addedand the mixture is centrifuged again. The cell pellet is resuspended in350 μl PI staining solution (0.1 mg/ml RNase A (Sigma, No. R-4875), 10μg/ml prodium iodide (Sigma, No. P-4864) in 1×PBS). The cells areincubated for 20 min in the dark with the staining buffer before beingtransferred into sample measuring containers for the FACS scan. The DNAmeasurement is carried out in a Becton Dickinson FACS Analyzer, with anargon laser (500 mW, emission 488 nm), and the DNA Cell Quest Programme(BD). The logarithmic PI fluorescence is determined with a band-passfilter (BP 585/42). The cell populations in the individual cell cyclephases are quantified using the ModFit LT Programme made by BectonDickinson.

The compounds according to the invention are also tested accordingly forother tumour cells. For example, these compounds are effective oncarcinomas of all kinds of tissue (e.g. breast (MCF7); colon (HCT116),head and neck (FaDu), lung (NCI-H460), pancreas (BxPC-3), prostate(DU145)), sarcomas (e.g. SK-UT-1B), leukaemias and lymphomas (e.g.HL-60; Jurkat, THP-1) and other tumours (e.g. melanomas (BRO), gliomas(U-87MG)) and could be used for such indications. This is evidence ofthe broad applicability of the compounds according to the invention forthe treatment of all kinds of tumour types.

The compounds of general formula (I) may be used on their own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances.

Suitable preparations include for example tablets, capsules,suppositories, solutions, particularly solutions for injection (s.c.,i.v., i.m.) and infusion, elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof. Excipients which may be used include, forexample, water, pharmaceutically acceptable organic solvents such asparaffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut orsesame oil), mono- or polyfunctional alcohols (e.g. ethanol orglycerol), carriers such as e.g. natural mineral powders (e.g. kaolins,clays, talc, chalk), synthetic mineral powders (e.g. highly dispersedsilicic acid and silicates), sugars (e.g. cane sugar, lactose andglucose) emulsifiers (e.g. lignin, spent sulphite liquors,methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g.magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may, of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples which follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

1. A method of treatment of a disease or condition responsive to aninhibitor of PLK, said disease or condition being selected from thegroup consisting of: cancer, infection, inflammation and an autoimmunedisease, said method comprising administering a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof the following formula (1):

wherein W denotes N or C—R², X denotes —NR^(1a), O or S, Y denotes CH, Zdenotes —CF₃; A is selected from one of the following formulas (i), (ii)and (iii):

Q₁ denotes that (i), (ii) and (iii) are mono- or bicyclic aryl; B¹, B²,B³ and B⁴ each independently of one another denote C—R^(g)R^(h),N—R^(i), O or S; R¹ and R^(1a) each independently of one another denotehydrogen or methyl; R² denotes one of hydrogen, halogen, —OR⁴, —C(═O)R⁴,—C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NR^(i), —SR⁴,—SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, pseudohalogen, and a mono- or polysubstitutedgroup selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆-cycloalkyl, aryl, heterocyclyl and heteroaryl, whereinthe substituent(s) of the mono- or polysubstituted group are identicalor different and are selected from the group consisting of halogen,—NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵,—NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴,—SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen; R^(a), R^(h),R^(e), R^(d), R^(e), R^(f), R^(g) and R^(h) each independently of oneanother denote a group selected from the group consisting of hydrogen,halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵,—NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵,—C═NR^(i), —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶,pseudohalogen, and an unsubstituted or mono- or polysubstituted groupselected from the group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, aryl, heterocyclyl and heteroaryl,wherein the substituent(s) of the mono- or polysubstituted group areidentical or different and are selected from the group consisting ofhalogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵,—NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴,—SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen;wherein R^(g) and R^(h) are optionally located at the same or atadjacent C atoms and are attached in any combination to a commonsaturated or partially unsaturated 3-5-membered alkyl bridge whichcontains one to two heteroatoms; R^(i) denotes a group selected from thegroup consisting of hydrogen, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵,—NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵,—SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶, pseudohalogenand an unsubstituted or substituted mono- or polysubstituted groupselected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, aryl, heterocyclyl and heteroaryl, whereinthe substituent(s) of the mono- or polysubstituted group are identicalor different and are selected from the group consisting of halogen, R⁸,—NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵,—NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴,—SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen; wherein the R^(i)groups located at adjacent N atoms are optionally joined together orR^(i) with R^(g) or R^(h) located at adjacent C atoms are optionallyattached in any combination to a common saturated or partiallyunsaturated 3-5-membered alkyl bridge which contains one to twoheteroatoms; R³ is selected from the following formulas (iv)-(x):

R⁴, R⁵ and R⁶ each independently of one another denote hydrogen or anunsubstituted or mono- or polysubstituted group selected from the groupconsisting of C₁₋₅-alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, C₃₋₁₀cycloalkyl,aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of themono- or polysubstituted group are identical or different and areselected from the group consisting of C₃₋₁₀-cycloalkyl, aryl,heterocyclyl, heteroaryl, halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸,—C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹,—NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen; L denotes a bond or anunsubstituted or mono- or polysubstituted group selected from the groupconsisting of C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein thesubstituent(s) of the mono- or polysubstituted group are identical ordifferent and are selected from the group consisting of halogen, —NO₂,—OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹,—NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹,—SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ andpseudohalogen; Q₂ and Q₃ each independently of one another denote a bondor an unsubstituted or mono- or polysubstituted group selected from thegroup consisting of C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein thesubstituent(s) of the mono- or polysubstituted group are identical ordifferent and are selected from the group consisting of halogen, —NO₂,—OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹,—NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹,—SR⁸, —SOR^(B), —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ andpseudohalogen; R⁷ denotes hydrogen or an unsubstituted or mono- orpolysubstituted group selected from the group consisting of C₁₋₁₆-alkyl,C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl andheteroaryl, wherein the substituent(s) of the mono- or polysubstitutedgroup are identical or different and are selected from the groupconsisting of halogen, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹,—NR⁸R⁹, —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰,—NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰,—OSO₂NR⁸R⁹ and pseudohalogen; and R⁸, R⁹ and R¹⁰ each independently ofone another denote hydrogen or a substituted or unsubstituted groupselected from the group consisting of C₁₋₈-alkyl, C₂₋₈alkenyl,C₂₋₈-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl,wherein the substituent(s) of the substituted group are identical ordifferent and are selected from the group consisting of halogen, methyl,ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen; or apharmacologically acceptable acid addition salt thereof in an excipientor carrier.
 2. A method of prevention of a disease or conditionresponsive to an inhibitor of PLK, said disease or condition beingselected from the group consisting of: infection, and inflammation; saidmethod comprising administering a therapeutically effective amount of apharmaceutical composition-comprising the compound the following formula(1):

wherein W denotes N or C—R², X denotes —NR^(1a), O or S, Y denotes CH, Zdenotes —CF₃; A is selected from one of the following formulas (i), (ii)and (iii):

Q₁ denotes that (i), (ii) and (iii) are mono- or bicyclic aryl; B¹, B²,B³ and B⁴ each independently of one another denote C—R^(g)R^(h),N—R^(i), O or S; R¹ and R^(1a) each independently of one another denotehydrogen or methyl; R² denotes one of hydrogen, halogen, —OR⁴, —C(═O)R⁴,—C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —C═NR^(i), —SR⁴,—SOW', —SO₂R⁴, —SO₂NR⁴R⁵, pseudohalogen, and a mono- or polysubstitutedgroup selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆-cycloalkyl, aryl, heterocyclyl and heteroaryl, whereinthe substituent(s) of the mono- or polysubstituted group are identicalor different and are selected from the group consisting of halogen,—NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵,—NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴,—SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen; R^(a), R^(h),R^(e), R^(d), R^(e), R^(f), R^(g) and R^(h) each independently of oneanother denote a group selected from the group consisting of hydrogen,halogen, ═O, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵,—NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵,—C═NR^(i), —SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶,pseudohalogen, and an unsubstituted or mono- or polysubstituted groupselected from the group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, aryl, heterocyclyl and heteroaryl,wherein the substituent(s) of the mono- or polysubstituted group areidentical or different and are selected from the group consisting ofhalogen, R⁸, —NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵,—NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴,—SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen;wherein R^(g) and R^(h) are optionally located at the same or atadjacent C atoms and are attached in any combination to a commonsaturated or partially unsaturated 3-5-membered alkyl bridge whichcontains one to two heteroatoms; R^(i) denotes a group selected from thegroup consisting of hydrogen, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵,—NR⁴R⁵, —NR⁴C(═O)R⁵, —NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵,—SR⁴, —SOR⁴, —SO₂R⁴, —SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶, pseudohalogenand an unsubstituted or substituted mono- or polysubstituted groupselected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, aryl, heterocyclyl and heteroaryl, whereinthe substituent(s) of the mono- or polysubstituted group are identicalor different and are selected from the group consisting of halogen, R⁸,—NO₂, —OR⁴, —C(═O)R⁴, —C(═O)OR⁴, —C(═O)NR⁴R⁵, —NR⁴R⁵, —NR⁴C(═O)R⁵,—NR⁴C(═O)OR⁵, —NR⁴C(═O)NR⁵R⁶, —NR⁴SO₂R⁵, —N═CR⁴R⁵, —SR⁴, —SOR⁴, —SO₂R⁴,—SO₂NR⁴R⁵, —NR⁴SO₂NR⁵R⁶, —OSO₂NR⁵R⁶ and pseudohalogen; wherein the R^(i)groups located at adjacent N atoms are optionally joined together orR^(i) with R^(g) or R^(h) located at adjacent C atoms are optionallyattached in any combination to a common saturated or partiallyunsaturated 3-5-membered alkyl bridge which contains one to twoheteroatoms; R³ is selected from the following formulas (iv)-(x):

R⁴, R⁵ and R⁶ each independently of one another denote hydrogen or anunsubstituted or mono- or polysubstituted group selected from the groupconsisting of C₁₋₅-alkyl, C₂₋₅alkenyl, C₂₋₅alkynyl, C₃₋₁₀cycloalkyl,aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of themono- or polysubstituted group are identical or different and areselected from the group consisting of C₃₋₁₀-cycloalkyl, aryl,heterocyclyl, heteroaryl, halogen, —NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸,—C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹,—NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ and pseudohalogen; L denotes a bond or anunsubstituted or mono- or polysubstituted group selected from the groupconsisting of C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein thesubstituent(s) of the mono- or polysubstituted group are identical ordifferent and are selected from the group consisting of halogen, —NO₂,—OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹,—NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹,—SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ andpseudohalogen; Q₂ and Q₃ each independently of one another denote a bondor an unsubstituted or mono- or polysubstituted group selected from thegroup consisting of C₁₋₁₆-alkyl, C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl,C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein thesubstituent(s) of the mono- or polysubstituted group are identical ordifferent and are selected from the group consisting of halogen, —NO₂,—OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹,—NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰, —NR⁸SO₂R⁹, —N═CR⁸R⁹,—SR⁸, —SOR^(B), —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰, —OSO₂NR⁸R⁹ andpseudohalogen; R⁷ denotes hydrogen or an unsubstituted or mono- orpolysubstituted group selected from the group consisting of C₁₋₁₆-alkyl,C₂₋₁₆-alkenyl, C₂₋₁₆-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl andheteroaryl, wherein the substituent(s) of the mono- or polysubstitutedgroup are identical or different and are selected from the groupconsisting of halogen, NO₂, —OR⁸, —C(═O)R⁸, —C(═O)OR⁸, —C(═O)NR⁸R⁹,—NR⁸R⁹, —NR⁸COR⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)ONR⁹R¹⁰,—NR⁸SO₂R⁹, —N═CR⁸R⁹, —SR⁸, —SOR⁸, —SO₂R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁹R¹⁰,—OSO₂NR⁸R⁹ and pseudohalogen; and R⁸, R⁹ and R¹⁰ each independently ofone another denote hydrogen or a substituted or unsubstituted groupselected from the group consisting of C₁₋₈-alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₁₀-cycloalkyl, aryl, heterocyclyl and heteroaryl,wherein the substituent(s) of the substituted group are identical ordifferent and are selected from the group consisting of halogen, methyl,ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen; or apharmacologically acceptable acid addition salt thereof in an excipientor carrier.